French Academic Strengths in Epigenetics and Cancer

Innovative Projects for International Business Opportunities
and R&D Collaborations
French academic
strengths in
epigenetics and cancer
Projects Book 2nd Edition
February 2016
Strategic Tech Transfer Field:
Therapeutic Innovation in Oncology
Yoann Schumacher, Ph.D., Project Manager
[email protected]
Melina Gaffré, Ph.D., Coordinator, Inserm Transfert
[email protected]
Introduction
T
he Thematic Tech Transfer Consortium (aka Consortium de Valorisation Thématique or
CVT in French) from the national alliance in life sciences, Aviesan, aims to coordinate
the policies, strengths and expertises of its stakeholders* in the fields of life science
and health. This is developed through several Strategic Tech Transfer Fields (aka Domaine
de Valorisation Stratégique or DVS in French) whose goal is to provide national analyses and
actions for their scientific and industrial communities, and to promote partnering opportunities.
The DVS “Therapeutic Innovation in Oncology”, in particular, is supported by Inserm Transfert
and Institut Curie and is dedicated to facilitate the transfer of academic innovations in oncology to the Industry. For this purpose, the DVS has focused its actions on two axis: the identification of novel and innovative epigenetic targets and the development of focalized therapies
for treating cancer.
Concerning the epigenetic targets, the mains objectives of the DVS are:
1. S
timulate and facilitate the setting up of partnerships between industrials and academics by:
> Mapping and gathering the French academic expertises in epigenetics
> Mapping both academic and industrial French Intellectual Property in epigenetic target
validation
> Analyzing industrial needs
> Identifying potential collaborative R&D projects
> Contributing to build, develop and maintain a trusted relation between academics and
industry
> Boosting the development of novel therapeutic approaches
2. Identify main technology transfer hurdles in this axis
3. Contribute to maintain the visibility of France in this innovative theme.
Directly in line with these objectives, the DVS “Therapeutic Innovation in Oncology” has gathered
in this book innovative projects to highlight French academic strengths in epigenetics and to:
> Enhance the visibility of French research in epigenetics
> Trigger collaborations between researchers
> Facilitate Industry-Academia Partnerships
2
SOMMAIRE
•> 4Geneviève ALMOUZNI & Zachary GURARDLEVIN
Chromatin Dynamics
•> 7
aola B. ARIMONDO
P
Epigenetic Targeting of Cancer
•> 10 C
atherine BAUGÉ
Chondrosarcomas: Physiopathology and Innovative
Therapies
•> 13 O
livier BERNARD
Normal and malignant hematopoises
•> 15 P
hilippe BERTRAND
HDAC inhibitors and their delivery
•> 17Pierre-François CARTRON
Design of a new generation of epidrugs targeting
certains selective interactions between an
epigenetic protein and one of its partner
•> 20Jean CAVARELLI
Structural Biology of Epigenetic Targets
•> 21Hervé CHNEIWEISS
Plasticity and Development of Human Brain Tumor
•> 24Françoise DANTZER & Valérie SCHREIBER
Poly(ADP-ribosyl)ation and genome integrity
•> 27Estelle DUPREZ
Epigenetic control of normal and pathological
hematopoiesis
•> 30 R
eini FERNANDEZ DE LUCO
Epigenetic and Alternative Splicing
•> 33 P
ierre Ferrier
Deciphering functional activity of TLX homeodomain
oncogenes in T-cell Acute Leukemia (T-ALL):
Epigenetic analysis
•> 34 H
inrich GRONEMEYER
Systems biology of cell fate decisions in normal and
tumor cells
•> 39Christophe François GROSSET
Regulation of Genes by microRNAs in Cancer and
Development
•> 42Dominique GUENOT
Impact of hypoxia and microenvironment in tumor
progression and response to treatment. Translational
approaches and epidemiology
•> 54 S
aadi KHOCHBIN
Epigenetic and Cell Signaling
•> 57 J osé Arturo Londo ño-Vallejo
Chromosome instability, epigenetics and microRNAs
•> 60Jérôme MOREAUX
Epigenetic and genomic instability mining in Multiple
Myeloma to define precision medicine
•> 63Antonin Morillon
lncRNA and cancer
•> 66Jean MOSSER
Integrated Functional Genomic and Biomarkers
•> 69 C
hristian MUCHARDT
Transcription and Splicing in the Context of
Chromatin
•> 72 P
eter MULLIGAN
Epigenetics and Cancer
•> 75Françoise OCHSENBEIN
Molecular assemblies and genome integrity
•> 78Benjamin ORY
Genetic and Epigenetic aspects of primary bone
tumors development and bone mineralization
•>82
Yves RENAUDINEAU
B cell diseases and epigenetics
•>85
Claire Rougeulle
Non-coding RNAs in development and disease
•>88
Jörg Tost
Laboratory for Epigenetics & Environment
•> 91 M
ichèle TRABUCCHI
Control of Gene Expression
•> 94 Isabelle VAN SEUNINGEN
Epigenetics and epithelial stemness, differentiation
and carcinogenesis
•> 97André VERDEL
RNA and Epigenetics
•> 99 T
hierry VIROLLE
Molecular basis of glioma cancer stem cells
properties and functional intra tumor heterogeneity
•> 102Bohdan WASYLYK
Molecular and Cellular Biology of HNSCC and
Prostate Cancer
•> 45Christel Guillouf
PU.1 transcription factor in epigenetic and splicing
regulation
•> 105Michael WEBER
Laboratory « Epigenetic Regulation of Cell Identity »
headed by Michael Weber
•> 48Zdenko HERCEG
Epigenome deregulation and cancer : mechanisms
and biomarkers
•> 108 Jonathan WEITZMAN
Epigenetics and Cell Fate
•> 51
Eric JULIEN
Functions of lysine methylation pathways
3
Chromatin Dynamics
Geneviève ALMOUZNI
& Zachary GURARD-LEVIN
Ph.D.
Contact: [email protected]
> Research Center; Town: Institut Curie, Paris
> Administrative affiliations: Institut Curie - CNRS UMR 3664
> Tech Transfer Office: Institut Curie
www.curie.fr
Keywords:
• Chromatin dynamics
• Chaperones
• Genome stability
• Centromeres
• Epigenetics
Synopsis:
Our team is interested in understanding how chromatin organization is established, propagated, maintained,
and changed during development and in response to environmental cues. Errors in these processes can lead
to mis-regulation of genome functions and pathological outcomes, such as cancer.
Abstract:
We study how chromatin organization is established, propagated, maintained, and changed during development
and in response to environmental cues. Errors in these processes can lead to mis-regulation of genome
function and pathological outcomes, such as cancer. We have dissected the mechanisms of chromatin
assembly, from the basic structural unit, the nucleosome, to higher-order nuclear structures. We revealed the
importance of key chaperones involved in nucleosome assembly including histone management and their
specific marks typical of particular chromatin domains. We integrate these findings with dynamic changes
during cell cycle/repair and differentiation and their consequences for nuclear organization and pathologies.
Selected references
Grants
• Various research / clinical grants, including 2 european research grants,
• Industrial collaboration,
• ERC grant.
Major publications over the past four years
• Montes de Oca R. et al. (2014) HJURP, a CENP-A chaperone as a new
prognostic factor in luminal A breast carcinoma. Mol. Oncol., in press.
Müller S. et al. (2014). Phosphorylation and DNA-binding of HJURP determine its centromeric recruitment and function in CenH3CENP-A loading.
Cell Rep., 8, 190-203.
Lacoste N. et al. (2014). Mislocalization of the centromeric histone variant
CenH3/CENP-A in human cells depends on the chaperone DAXX. Mol.
Cell, 53, 631-644.
Adam S. et al. (2013). Transcription recovery after DNA damage requires
chromatin priming by the H3.3 histone chaperone HIRA. Cell, 155, 94-106.
Casanova M. et al. (2013). Heterochromatin reorganization during early
mouse development requires a single-strand non-coding transcript. Cell
Rep., 4, 1156-1167.
Patents
• 4 patients available for licencing.
4
Chromatin Dynamics
Geneviève ALMOUZNI
& Zachary GURARD-LEVIN
Business Development Opportunities
Objectives:
• We study how chromatin organization is established, propagated, maintained, and
changed during development and in response to environmental cues. Errors in these
processes can lead to mis-regulation of genome function and pathological outcomes,
such as cancer.
Tools:
• SNAP-tagging and imaging
• ChIP and ChIP-seq
• RNA interference in cultured cells
• Protein complexes purification from cells stably expressing tagged-factors
• Micro-injection / manipulation of Xenopus and mouse early embryos (2 cell stage) and
follow-up of development
• Advance 3D and time-lapse fluorescence microscopy
• Transgenic / KO mouse models
• Bio-computing analysis of high-throuput sequencing / expression data
• Analysis of the dynamics of factors in vivo by SNAP-Tag and imaging including FRAP,
local damage
• Annotated samples, tumor library
• Cohort of patients with their follow-up
Unique selling points:
•O
ur team has over 20 years of expertise in chromatin, nuclear organization, replication
repair and development.
•W
e have dissected the mechanisms of chromatin assembly, from the basic structural
unit, the nucleosome, to higher-order nuclear structures. We revealed the importance
of key chaperones involved in nucleosome assembly including histone management
and their specific marks typical of particular chromatin domains. We integrate these
findings with dynamic changes during cell cycle/repair and differentiation and their
consequences for nuclear organization and pathologies.
5
Chromatin Dynamics
Geneviève ALMOUZNI
& Zachary GURARD-LEVIN
Project / Expertise
CHAPTAR
Results
• Design of specific inhibitor of a histone chaperone and its applications in breast cancer
therapy
Perspectives
• Extend the approach for other applications to
new challenging new target in the epigenetic
area
6
Epigenetic Targeting
of Cancer
Paola B. ArimondO
Ph.D.
Contact: [email protected]
> Research Center; Town: C
entre de recherche et de
développement Pierre Fabre
(CRDPF), Toulouse
> Administrative affiliations: CNRS - Pierre Fabre USR 3388
> Tech Transfer Office: Toulouse Tech Transfert
www.toulouse-tech-transfer.com
Keywords:
• DNA methylation
• Histone methylation
• Medicinal chemistry
• Pharmacology
• Chemical Biology
Synopsis:
We carry out pluridisciplinary approaches spanning from chemistry to biology in the field of epigenetics to
identify new therapeutical agents and targets to fight cancer.
Abstract:
Epigenetics defines when and where genes are expressed. Epigenetic marks are reversible and inheritable,
integrate the impact of the environment and provide cellular plasticity. Aberrant epigenetic patterns are
involved in tumor formation and maintenance. Notably, epigenetic modifications can be modified by chemical
agents. Recently, several epigenetic chemical agents entered clinical trials to treat hematological tumors.
Our research projects combine exploratory aspects (as the research of new biological mechanisms and
targets) and applied ones (drug candidates discovery) in the field of Cancer Epigenetics. More specifically,
our projects are focused on innovation in terms of
1) Chemistry with the synthesis of novel oriented chemical libraries to target DNA and histone
methyltransferases in cell;
2) Chemical Biology to identify the target of the bioactive molecules in cancer cells upon use of chemical
probes and
3) pharmacological strategy to reprogram epigenetically the cancer cells to a less aggressive state and more
sensitive to chemotherapy and immunotherapy.
Selected references
Grants
• PlanCancer 2014-2017, EpiChemSeq
•
Fondation InnaBioSanté 2013-2015, Epigenetic Aggressivity of Melanoma
• ATiP CNRS (2010-2012) and Equipe d’Excellence Midi Pyrenées 20112013, Targeing DNA methylation
Major publications over the past four years
• Ceccaldi A, et al.ACS Chem Biol. 2013 8(3):543-8
• Moison C, e et al.. FASEB J. 2013 27(4):1468-78
• Erdmann A, et al. J Med Chem. 2015 58(6):2569-83
• Gros C, et al. J Biol Chem 2015 290(10):6293-302.
• Vispé S, et al. OncoTarget 2015 6(17):15265-82.
Patents
• Ceccaldi A., Sénamaud-Beaufort C., Jurkowska R., Gagey N., Dauzonne
D., Jeltsch A., Guianvarc’h D., Arimondo P.B. N° Dépôt °09305840.2, September 14, 2009.
• Halby, L.; Guianvarc’h, D.; Sénamaud-Beaufort, C.; Ferroud, C.; Grellier, P.;
Arimondo, P.B., N° Dépôt: 10306004, 20/09/2010.
• Halby, L.; Arimondo, P.B., N° Dépôt: EP13306073. 24/07/2013.
WO2015040169
7
Epigenetic Targeting
of Cancer
Paola B. ArimondO
Business Development Opportunities
8
Epigenetic Targeting
of Cancer
Paola B. ArimondO
Project / Expertise
Epigenetic Reprogramming of Leukemia
Study of the epigenetics of Leukemia Initiating Cells (LIC) in the context of the microenvironment and their interplay
in AML and CLL chemoresistance.
Aims:
• The short-term application of the project is the development of HCS technology for epigenetic impact characterisation resulting in a standardized methodology/kit/service for patients stratification in AML and CLL for epidrug treatment
• Long-term applications are to find new treatments to fight leukaemia, in particular to eradicate LICs causing relapse
and improvement of the safety of the treatments.
Partners:
Dr François ICHAS,
Fluofarma, Pessac
Dr. Anne QUILLET-MARY,
Dr. Jean-Emmanuel SARRY
CRCT, Toulouse
Prof. Louis CASTEILLA
STROMALab, Toulouse
9
Chondrosarcomas:
Physiopathology and
Innovative Therapies
Catherine Baugé
Ph.D.
Contact: [email protected]
> Research Center; Town: Caen
> Administrative affiliations: Université de Caen EA4652
> Tech Transfer Office: Université de Caen
www. recherche.unicaen.fr
Keywords:
• Hypoxia
• Genetics/epigenetics
• in vitro and in vivo models
Laboratory research area
Cartilage and associated diseases
Chondrosarcomas:
- mechanism of resistance to treatments (chemotherapy and radiotherapy)
- innovative therapies (epigenetics; hadrontherapy)
Abstract
Chondrosarcomas (CHS) are malignant tumors of bone that produce hyaline cartilage matrix. Primary CHS
is the second most frequently primary malignant tumor of bone after osteosarcoma, and represents about
25% of bone sarcomas. CHS is considered as highly resistant to both chemotherapy and radiations, making
surgical resection the only curative treatment. However, mechanisms of resistance are not well understood.
Our first project aims to investigate resistance mechanism to radiotherapy and chemotherapy. We compared
the response of five different chondrosarcoma cell lines to X-ray radiation and cisplatin. We showed that
chondrosarcoma lines respond differently to treatments. In addition, our study is the first one which extensively
characterizes commonly used human CHS cell lines by exome sequencing. These genetic data provide
essential information on resistance mechanisms. Environmental factors such as hypoxia are also studied.
Our second project aims to identify new strategies to treat chondrosarcomas. In particular, we focus on
epigenetic therapy. We showed that high grade chondrosarcomas highly express the histone methylase
EZH2, when compared to enchondromas or chondrocytes. In addition, we showed that DZNep inhibits
EZH2 protein expression and reduces H3K27me3 in some CHS, leading to cell death by apoptosis in vitro
and in vivo. These results indicate that DZNep may be an interesting molecule to treat chondrosarcomas.
However, its mechanism action is still under investigation.
Selected references
Grants
• FHU “SURFACE” (2015-2020)
• PHRC “Exorhum” (2014 – 2020)
• Emerging Programme “CAEn” (Region Basse-Normandie : 2014-2016)
• FP6 “Genostem”
Major publications over the past four years
• Manna et al. Histone H3 Lysine 27 demethylases Jmjd3 and Utx are required for T cell differentiation. Nature Commun 2015 (accepted)
• Baugé, Boumediene. Use of adult stem cells for cartilage tissue engineering: current status and future developments. Stem cells Int 2015 (in press)
• Baugé et al. Histone methylases as novel drug targets: developing inhibitors of EZH2. Future Med Chem 2014; 6(17), 1927-1948
• Girard et al.. 3-deazaneplanocin A (DZNep), an inhibitor of the histone
methyltransferase EZH2, induces apoptosis and reduces cell migration in
chondrosarcoma cells. Plos One 2014 May;9(5): e98176.
• Duval et al. Molecular mechanism of hypoxia induced chondrogenesis and
its application in in vivo cartilage tissue engineering. Biomaterials 2012
Sep;33(26):6042-51.
10
Chondrosarcomas:
Physiopathology and
Innovative Therapies
Catherine Baugé
Business Development Opportunities
Objectives:
• Identification of new therapeutic targets for cartilage associated-diseases
(chondrosarcomas and osteoarthritis)
• Understanding the role of H3K27 methylation in cartilage during development, ageing
and diseases.
Tools:
• Cellular and molecular biology
• Biochemistry
• Animal models
• Transcriptomics, NGS, bioinformatics
Unique selling points:
• Team nationally and internationally recognized for its expertise in cartilage biology and
tissue engineering (EU, ANR, FHU…)
• Multidisciplinary team (cell biology, physiology, genetics, bioinformatics scientists;
pathologists, anatomists, rheumatologists, orthopaedic surgeons…)
• Original models for study
- chondrogenesis without interference with serum or growth factor
- OA chondrocytes (primary culture)
- chondrosarcomas (cell lines and primary cells) with complete molecular
characterizations (full exome sequencing)
• Access to conditional KO mice for histone demethylases
11
Chondrosarcomas:
Physiopathology and
Innovative Therapies
Catherine Baugé
Project / Expertise
H3K27me3 in cartilage tumoral cells
(chondrosarcomas)
Results
• The histone methylase EZH2 is highly expressed in high
grade chondrosarcomas. Its inhibition by DZNep induced
chondrosarcoma death in vitro and in vivo.
Perspectives
• Validate results with more chondrosarcomas
• Confirm data with additional animal models
• Identify molecular mechanism involved
• Role of histone demethylases ?
H3K27me3 in osteoarthritis (OA)
cartilage
Results
• DZNep reduces inflammation in OA cartilage
Perspectives
• Identify all target pathways of DZNep in
chondrocytes
• Validate data in OA animal models
• Improve cartilage tissue engineering, and/
or pharmaceutical treatment of OA
• Study role of the histone methylase EZH2,
and demetylase JMJD3 and UTX in chondrogenesis, aging and OA process.
12
Normal and malignant
hematopoises
Olivier BERNARD
Ph.D.
Contact: [email protected]
> Research Center; Town: Institut Gustave Roussy, Villejuif
> Administrative affiliations: Institut Gustave Roussy, Inserm,
Université Paris Saclay
> Tech Transfer Office: Gustave Roussy Transfert
www.gustaveroussy.fr/en/content/technology-transfer-overview
Keywords:
• Stem cell biology
• Megakaryocytic differentiation
• Erythroid differentiation
• Acute leukemia
• Lymphoproliferative disorders
• Lymphoma
• Genetics and epigenetics
• Transcription control
• Modeling
• Mutant IDH proteins
• TET proteins
• Clinical trials
Synopsis
The unit is conducting an integrated approach of malignant and benign hematology, including clinical trials,
thorough analyses of primary samples and modelling in human and mouse contexts, using cutting edge
technologies.
Abstract:
We are investigating the mutations landscape in human malignancies, including non-malignant
megakaryocytosis, acute myeloblastic leukemia, chronic myelomonocytic leukemia, myeloproliferative
neoplams, lymphoproliferative disorders and lymphomas. This includes both acquired and germinal variant
and lead to the identification of «druggable» targets that are tested in early phase clinical trials. The genomic
results lead to modeling in mouse and human cells for functional analyses and pre-clinical trials
Selected references
Major publications over the past four years
• TET2 inactivation results in pleiotropic hematopoietic abnormalities in
mouse and is a recurrent event during human lymphomagenesis. Quivoron
et al. Cancer Cell. 2011 Jul 12;20(1):25-38.
• Mutation in TET2 in myeloid cancers. Delhommeau et al. N Engl J Med.
2009 May 28;360(22):2289-301
• Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Wanget al. Science. 2013 May 3;340(6132):622-6
• Serum 2-hydroxyglutarate production in IDH1- and IDH2-mutated de
novo acute myeloid leukemia: a study by the Acute Leukemia French Association group. Janin et al. J Clin Oncol 2014;32:297-305.
• Characterization of novel genomic alterations and therapeutic approaches
using acute megakaryoblastic leukemia xenograft models. Thiollier et al. J
Exp Med. J Exp Med 2012;209:2017-31.
13
Normal and malignant
hematopoises
Olivier BERNARD
Business Development Opportunities
Objectives:
• We are investigating the mutations landscape in human malignancies, including nonmalignant megakaryocytosis, acute myeloblastic leukemia, chronic myelomonocytic
leukemia, myeloproliferative neoplams, lymphoproliferative disorders and lymphomas. This
includes both acquired and germinal variant and lead to the identification of «druggable»
targets that are tested in early phase clinical trials. The genomic results lead to modeling
in mouse and human cells for functional analyses and pre-clinical trials
Tools:
• Exceptional continuum between clinics and research
• Clinical structure dedicated to clinical trials
• 17 ongoing clinical trials (single agents and combinations)
• All aspect of cellular and molecular murine and human hematology
• Next generation sequencing (exome, RNA-seq,ChIP-Seq)
• FACS analyses
• Cell sorting
• Xenografts
14
HDAC inhibitors
and their delivery
Philippe BERTRAND
Ph.D, Associate professor
Contact: [email protected]
> Research Center; Town: Institut de Chimie de Milieux et
Matériaux de Poitiers (IC2MP),
Poitiers
> Administrative affiliations: IC2MP team 5 organic synthesis,
Université de Poitiers, CNRS
> Tech Transfer Office: SATT Grand Centre
www.sattgc.com
Keywords:
• Chemical biology of epigenetics
• Epigenetic target inhibitor synthesis
• Drug delivery, prodrugs
Attractive synopsis
Our original research focus on synthesis of epigenetic targets inhibitors by means of superacid chemistry
and green processes, coupled to simplified strategies for pH-mediated delivery
Abstract
The work is applied in oncology (mesothelioma and myeloma). The expertise of the team is organic synthesis
in general, asymmetric and total synthesis in particular, using all available methods in the field (micro waves,
superacid, chiral resolution, greener catalytic transformation of building blocks….). The research strategy is
currently focusing on acetylation dynamics in cellular environments as the major mechanism of action of our
compounds, major data include successful application of selective delivery of histone deacetylase inhibitors
in mesothelioma in vivo. Developing this current knowledge to develop more specific histone deacetylases
inhibitors and novel ways for delivery connected to diagnostics
Selected references
Grants
• ANR 2009-2011, Ligue, Region Poitou-Charentes
Major publications over the past four years
• Biomacromolecules 2013, 14, 2396−2402
• Biomacromolecules 2014, 15, 4534−4543
• Oncotarget, 2014, 5, 4504
• Eur. J. Pharm. Biopharm. 85 (2013) 862–872
• Eur. J. Med. Chem. 95 (2015) 369
Patents
• US2014/0219925 A1
15
HDAC inhibitors
and their delivery
Philippe BERTRAND
Business Development Opportunities
Objectives:
• Synthesis of epigenetic targets inhibitors
• Chemistry for delivery
Tools:
• All tools needed for organic synthetic chemistry including chiral molecules
16
Design of a new generation of
epidrugs targeting certains selective
interactions between an epigenetic
protein and one of its partner
Pierre-François CARTRON
Ph.D.
Contact: [email protected]
> Research Center; Town: C
entre de recherche en cancérologie
Nantes-Angers (CRCNA) Nantes
> Administrative affiliations: Inserm UMRS 892 - CNRS 6299
> Tech Transfer Office: Inserm Transfert
www.inserm-transfert.fr
Keywords:
• DNA methylation / demethylation
• Histone post-translational modifications :
phosphorylation
• Apoptosis
• Glioma, lung and brest cancers
Laboratory research area
Establishment of an epigenetic therapy targeting the writers of epigenetics signatures associated with
a phenotype of apopto-resistance to standard anticancer therapies in order to restore efficiency of this
anticancer treatment.
Synopsis
Design of a new generation of epidrugs targeting certains selective interactions between an epigenetic
protein and one of its partner.
Selected references
Grants
• “Canceropole Grand Ouest”
• “Ligue contre le Cancer”
Major publications over the past four years
• Cheray M, Pacaud R, Nadaradjane A, Oliver L, Vallette FM and Cartron PF.
Specific inhibition of DNMT3A/ISGF3g interaction increases temozolomide
efficency by reducing tumor growth. Theranostics. In press.
• Pacaud R, Cheray M, Nadaradjane A, Vallette FM, Cartron PF. Histone H3
phosphorylation in GBM: a new rational to guide the use of kinase inhibitors
in anti-GBM therapy. Theranostics. 2015 Jan 1;5(1):12-22. • Cheray M, Nadaradjane A, Bonnet P, Routier S, Vallette FM, Cartron PF.
Specific inhibition of DNMT1/CFP1 reduces cancer phenotypes and enhances chemotherapy effectiveness. Epigenomics. 2014 Jun;6(3):267-75.
• Pacaud R, Sery Q, Oliver L, Vallette FM, Tost J, Cartron PF. DNMT3L interacts with transcription factors to target DNMT3L/DNMT3B to specific
DNA sequences: role of the DNMT3L/DNMT3B/p65-NFkB complex in
the (de-)methylation of TRAF1. Biochimie. 2014 Sep;104:36-49.
• Pacaud R, Brocard E, Lalier L, Hervouet E, Vallette FM, Cartron PF. The
DNMT1/PCNA/UHRF1 disruption induces tumorigenesis characterized by
similar genetic and epigenetic signatures. Sci Rep. 2014 Mar 18;4:4230.
• Cartron PF, Nadaradjane A, Lepape F, Lalier L, Gardie B, Vallette FM. Identification of TET1 Partners That Control Its DNA-Demethylating Function.
Genes Cancer. 2013 May;4(5-6):235-41.
• Cheray M, Pacaud R, Nadaradjane A, Vallette FM, Cartron PF. Specific
inhibition of one DNMT1-including complex influences tumor initiation and
progression. Clin Epigenetics. 2013 Jun 28;5(1):9. doi: 10.1186/18687083-5-9.
Patents
• New method for treating and prognosing cancer (EP15305314.5).
17
Design of a new generation of
epidrugs targeting certains selective
interactions between an epigenetic
protein and one of its partner
Pierre-François CARTRON
Business Development Opportunities
Objectives:
• Identification, in cohort of cancer-patients of epigenetic actor-including complexes
(EpAICs) whose presence is associated with poor prognosis.
• Identification of peptides, compounds and/or design of small molecules able to
specifically disrupt EpAICs of interest (named Selective Epigenetic Drug, SED).
• Validation of SEDs in cellular and in vivo models and identification of the role played by
the EpAICs of interest during development.
Tools:
• Biobank of tumors (Glioma, prostate, breast,…)
• Expertise on several epigenetic actors: DNMTs, HDACs, histone kinases, Brd proteins.
• Expertise on the identification, characterization, monitoring of protein-protein
interactions via mastery of a large panel of methods (immunoprecipitation, pull down,
competitive pull down, Biacore, P-LISA, BRET, epitope mapping, nuclear micro-injection).
• Expertise on devleopment of peptide inhibiting protein-protein interaction.
Unique selling points:
• Bank of peptide inhibiting specific protein-protein interactions such as DNMT1/PCNA,
DNMT/UHRF1, DNMT1/CFP1…
• Expertise on protein-protein interaction: epitope mapping method.
• Expertise on cellular microinjection.
18
Design of a new generation of
epidrugs targeting certains selective
interactions between an epigenetic
protein and one of its partner
Pierre-François CARTRON
Project / Expertise
Results
• The 1081-1097DNMT1 peptide, a peptide down-regulating
the formation of the DNMT1/
CFP1 interaction, enhances the
antitumor effect of a TMZ treatment.
Perspectives
• Development of peptide or
molecule disrupting selective
DNMT1/CFP1 interaction
After the induction of tumor (volume =
100mm3) by the subcutaneous injection of
U251 cells, mice were treated 5 days per
week during
6 weeks with the indicated treatment.
The asterisk (*) indicates the presence
of significant modulations in the tumor
weight between the considered conditions
according to the realization of the t-test (p
< 0.05).
Graphs illustrate the average ± standard
deviation of tumor weight obtained by
considering the treatment of five mice per
condition.
Source: Cheray M, Nadaradjane A,
Bonnet P, Routier S, Vallette FM, Cartron
PF. Specific inhibition of DNMT1/CFP1
reduces cancer phenotypes and enhances
chemotherapy effectiveness.Epigenomics.
2014 Jun;6(3):267-75. PMID: 25111481.
Results
• By focusing on interactions existing between
DNMT3A and DNMT3A-binding protein (D3ABP), our work identifies the DNMT3A/ISGF3γ
interaction such as a biomarker whose the presence level is associated with a poor survival prognosis and with a poor prognosis of response
to the conventional chemotherapeutic treatment
of glioblastoma multiforme (radiation plus temozolomide). Our data also demonstrates that the
disruption of DNMT3A/ISGF3γ interactions
increases the efficiency of chemotherapeutic
treatment on established tumors in mice.
Perspectives
• Development of peptide or molecule disrupting
selective DNMT3A/ISGF3γ interaction
19
Structural biology of
epigenetic targets
Jean Cavarelli
Ph.D, Pr.
Contact: [email protected]
> Research Center; Town: Institut de Génétique et de Biologie
Moléculaire et Cellulaire (IGBMC)
Strasbourg
> Administrative affiliations: C
NRS UMR 7104 - Inserm U 964 Université de Strasbourg
> Tech Transfer Office: Conectus
www.conectus.fr
Keywords:
• Arginine methylation
• Structure-based drug design
• Crystallography
Synopsis
Our team has a solid background in structural biology and develops within the ChemStrAppPRMTs consortium
chemical tools to understand Protein Aginine Methyl Transferase substrate recognition specificity, selectivity
and molecular mechanism providing lead compounds for epigenetic inhibitor discovery.
Abstract
Our team research is focusing on the understanding of the structure/function relationships of epigenetic
targets at the atomic level. The goals are to decipher at the molecular level the mechanisms governing
epigenetic processes mainly (but not only) by using information provided at the atomic level by X-ray
crystallography. Our team gathers expertise covering several aspects of modern structural biology, including
the reconstitution of macromolecular complexes by multi-expression, the characterization of protein and
macromolecular complexes by biophysical and structural means, and the modeling and design of lead
targets. We are developing structure-based rational approaches to characterize small molecule modulators
of the biological activities of our targets since they are frequently involved in human diseases. Our team also
participates in collaborative research on the structural studies of complexes involving cancer-related targets.
Selected references
Major publications over the past four years
• Functional insights from high resolution structures of mouse protein arginine methyltransferase 6.
Bonnefond L, Stojko J, Mailliot J, Troffer-Charlier N, Cura V, Wurtz JM, Cianférani S, Cavarelli J.
J Struct Biol Aug 2015 ; 191:175-83.
• Molecular Basis for the Antiparasitic Activity of a Mercaptoacetamide
Derivative That Inhibits Histone Deacetylase 8 (HDAC8) from the Human
Pathogen Schistosoma mansoni.
Stolfa DA, Marek M, Lancelot J, Hauser AT, Walter A, Leproult E, Melesina
J, Rumpf T, Wurtz JM, Cavarelli J, Sippl W, Pierce RJ, Romier C, Jung M.
J Mol Biol 9 octobre 2014 ; 426:3442-53.
• Structure of the Elongator cofactor complex Kti11/Kti13 provides insight
into the role of Kti13 in Elongator-dependent tRNA modification.
Kolaj-Robin O, McEwen AG, Cavarelli J, Séraphin B.
FEBS J Mar 2015 ; 282:819-33.
• Cloning, expression, purification and preliminary X-ray crystallographic
analysis of mouse protein arginine methyltransferase 7.
Cura V, Troffer-Charlier N, Lambert MA, Bonnefond L, Cavarelli J.
Acta Crystallogr F Struct Biol Commun Jan 2014.
• Structural insight into arginine methylation by the mouse protein arginine
methyltransferase 7: a zinc finger freezes the mimic of the dimeric state into
a single active site.
Cura V, Troffer-Charlier N, Wurtz JM, Bonnefond L, Cavarelli J.
Acta Crystallogr D Biol Crystallogr 1 septembre 2014 ; 70:2401-12.
• Structural Basis for the Inhibition of Histone Deacetylase 8 (HDAC8), a
Key Epigenetic Player in the Blood Fluke Schistosoma mansoni.
Marek M, Kannan S, Hauser AT, Moraes Mourão M, Caby S, Cura V, Stolfa
DA, Schmidtkunz K, Lancelot J, Andrade L, Renaud JP, Oliveira G, Sippl W,
Jung M, Cavarelli J, Pierce RJ, Romier C.
PLoS Pathog Sep 2013 ; 9:e1003645.
20
Plasticity
and development
of human brain tumor
Hervé CHNEIWEISS
MD, Ph.D.
Contact: [email protected]
> Research Center; Town: Institut de Biologie Paris Seine
(IBPS) Paris
> Administrative affiliations: C
NRS UMR 8246 - Inserm
U1130 - Université Pierre et
Marie Curie
> Tech Transfer Office: SATT Lutech
www.sattlutech.com
Keywords:
• Glial plasticity
• Brain tumor development
• Cancer stem cells
• Epigenetics
• Proteomics
Synopsis
The team relies on an integrated approach comprising the analysis of epigenetic marks regulation, paracrine
dialogue and metabolic pathways in cells derived from patients in order to understand the mechanism of
brain tumor development.
Abstract
Glioblastomas are the most common form of primary brain tumors, and the most aggressive: they resist to
current therapies and the median survival of the patients is shorter than 18 months. The team contributed
to build the model of cancer stem cells, and focuses now its effort on understanding the mechanisms
underlying stemness regulation in this context. Using cells derived from patients, the team explored the
interplay between epigenetic marks and metabolic pathway. Noteworthy, the researchers i) firstly involved
TGF-α in the dedifferentiation of astroctytes; ii) highlighted the importance of environment secretome in the
maintenance of the stemness and iii) identified a cluster of miRNA governing the epigenetic fingerprint of
cancer stem cells. In his ambition to find new therapeutic approaches against glioma, Hervé Chneiweiss is
strongly dedicated to transfer technology.
Selected references
Grants
• INCa PLBIO 2013-15 (>200k€)
• ARC Fundation 2013-2014 and 2007-2008 (>50k€)
• La Ligue 2013-2015 and 2007-2009 (>200k€)
Patents
• WO2014/202776: GHB derivatives for use in the treatment of cancer
• WO2012/168885: Bisacodyl as drugs for treating cancer
• WO2012/0110768: Use miRNA 302-367 cluster to treat cancer
Major publications over the past four years
• Metabolic reprogramming: Bentaib, et al., 2015. J Proteomics
• Orthotopic xenografts in mice: Jeitany, et al., 2015. Int J. Cancer
• Epigenetic regulation: Sayd, et al., 2014. Stem Cell Rev.
• Roles of miRNAs in stemness: Fareh, et al., 2012. Cell Death Differ.
• Secretome analysis: Thirant, et al., 2012. Stem Cells
• Glioma Stem Cell model: Thirant, et al., 2011. Plos One
21
Plasticity
and development
of human brain tumor
Hervé CHNEIWEISS
Business Development Opportunities
Objectives:
• Understanding the role glial plasticity in glioma development
• Characterizing tumor leaders: Glioma Stem Cell (GSC)
• Identifying compounds toxic for GSC or restricting their aggressive properties
Tools:
• Collection of glioma stem cells derived from adult and pediatric patients
• Animal model: mice with orthotopic xenografts
• Optical imagery tools to monitor cultured cells
• Flow cytometry to selected subpopulations of GSC
• Quantitative Proteomics: 2D-DIGE followed by mass spectrometry
• Metabolic analysis. Epigenetic analysis.
Unique selling points:
• Privileged access to cancer cells derived from adult and pediatric glioma
• Expertise at the molecular and functional level on Glioma Stem Cells (GSC)
• Integrated approaches via multiple collaborations: transcriptome and metabolome
profiling, epigenetic regulations, and proteomics
• International acknowledgement for the GSC model (4 reviews)
• Editorial boards: Progress in Neurobiology, Médecine/Sciences (ed. in chief)
• Involvement in administration and regulation:
Sit at the Ethic committee of Inserm, and at the national advisory board for bioethics
Sit at the Office Parlementaire d’évaluation des choix scientifiques et technologiques
22
Plasticity
and development
of human brain tumor
Hervé CHNEIWEISS
Project / Expertise
Development and plasticity of glioma: The Glioma Stem Cell (GSC) model
Results
• Cells derived from pediatric glioma show selfrenewal properties
• Tumor cells with prolonged self-renewal properties are associated with poor patient outcome,
and resistance
• Pediatric derived oncospheres have the ability
to form highly invasive tumors when xenografted
in mice brain
Perspectives
• Pediatric and adult glioma show similar root
causes
• Therapeutic anti-cancer strategies should take
cell plasticity into account
Dissecting the molecular mechanisms governing stem properties of GSC
Results
• Identification of the miR-302-367 cluster: its expression is
sufficient to suppress the stemness signature of Glioma Stem
Cells (GSC)
• Epigenetic alterations of the expression of miR-302-367: differential expression (down- or up-regulation of >300 genes)
• Metabolic alterations of the expression of miR-302-367:
GHB production is increased
Perspectives
• miR-302-367 appears as an interesting target for therapies
aiming to suppress GSC stem properties
• Therapeutic potential of GHB: treatment with GHB can recapitulate the loss of stemness in GSC
23
Poly(ADP-ribosyl)ation
and genome integrity
Françoise DANTZER
Valérie SCHREIBER
Ph.D.
Contact: [email protected]
Contact: [email protected]
> Research Center; Town: Institut de Recherche de l’Ecole
de Biotechnologie de Strasbourg
(IREBS), Illkirch
> Administrative affiliations: UMR7242 - CNRS - Université
de Strasbourg
> Tech Transfer Office: SATT Conectus Alsace
[email protected]
Keywords:
• poly(ADP-ribosyl)ation
• DNA repair and genome stability
• cell division and differenciation
• glioblastomas, breast cancers
Synopsis:
The aim of our team is to decipher the complex role of poly(ADP-ribosyl)ation reactions in the mechanisms
governing genome stability and tumorigenesis
Abstract:
Regulation of poly(ADP-ribose) produced by PARPs in response to DNA insults and degraded by PARG is
critical for the outcome of the damaged cell. PARP inhibitors are engaged in clinical trials for their promising
potentializing effect in chemo- and radiotherapy and one molecule has been approved for its cytotoxic effect
on repair-deficient (BRCA-mutated) advanced ovarian cancers. We have recently revealed an essential role
of PARP-3 and PARG in the cell recovery from DNA damage or replicative stress and in mitotic progression
and cell differentiation. Our goal is to decipher the biological role of PARP-3 and PARG in the maintenance
of genome integrity and in tumorigenesis, with the aim of determining the value of their pharmacological
targeting in cancer therapies. In light with this objective, we also develop strategies to generate specific
inhibitors of PARP-3 and PARG.
Selected references
Grants
• LabEX Medalis (2011-2020)
• Equipe labellisée Ligue (2011-2015)
• ANR (2014-2017)
• FRM (2015-2017)
• Ligue (2016), ARC (2016-2017), EDF (2016)
Major publications over the past four years
• Schreiber V, Illuzzi G, Héberlé E and Dantzer F (2015) De la découverte du
poly(ADP-ribose) aux inhibiteurs PARP en thérapie du cancer. Bull Cancer,
102, 863-73
• Robert I, Gaudot L, Rogier M, Heyer V, Noll A, Dantzer F, Reina-San-Martin
B. (2015). Parp3 negatively regulates immunoglobulin class switch recombination. PLoS Genet, 22;11(5):e1005240. doi: 10.1371.
• Illuzzi G, Fouquerel E, Amé JC, Noll A, Rehmet K, Nasheuer HP, Dantzer
F and Schreiber V (2014). PARG is dispensable for recovery from transient replicative stress but required to prevent detrimental accumulation
of poly(ADP-ribose) upon prolonged replicative stress. Nucleic Acids Res.
42,7776-92
• Beck C, Boehler C, Barbat JG, Bonnet ME, Illuzzi G, Ronde P, Gauthier LR,
Magroun N, Rajendran A, Lopez BS, Scully R, Boussin FD, Schreiber V and
Dantzer F (2014). PARP3 affects the relative contribution of homologous
recombination and nonhomologous end-joining pathways. Nucleic Acids
Res. 2014;42(9):5616-32
• De Vos M, El Ramy R, Quénet D, Wolf P, Spada F, Magroun N, Babbio F,
Schreiber V, Leonhardt H, Bonapace IM and Dantzer F (2014) Poly(ADPribose) polymerase 1 (PARP1) associates with E3 ubiquitine-protein ligase UHRF1 and modulates UHRF1 biological functions. J. Biol. Chem.
289(23):16223-16238
• Beck C, Robert I, Reina San Martin B, Schreiber V and Dantzer F (2014).
Poly(ADP-ribose) polymerases in double-strand break repair : focus on
PARP1, PARP2 and PARP3. Exp. Cell Res. 329(1):18-25.
• Le May N, Iltis I, Amé JC, Zhovmer A, Biard D, Egly JM, Schreiber V* and
Coin F* (2012) Poly(ADP-ribose) glycohydrolase regulates retinoic acid
receptor-mediated gene expression. Mol Cell 48, 785-798.
24
Poly(ADP-ribosyl)ation
and genome integrity
Françoise DANTZER
Valérie SCHREIBER
Business Development Opportunities
Objectives:
• Role of PARPs and PARG in the maintenance of genome integrity
• Role of PARP3 in cell fate
• Defining the interest of targeting PARP3 and PARG in cancer therapy
• Biochemical characterisation of PARP-3 enzymatic activity
• Deciphering the in vivo regulation of PARG activity
• Generation of PARP-3 and PARG specific inhibitors
Tools:
• Cellular and animal models (KO, CRISPr-Cas9, shRNA)
(Parp-1-/-, Parp-2-/-, Parp-3-/-, Parp-9-/-; Parp-1-/-;Parp-2flox; Parp-1-/-;Parp-3-/-…)
• PARPs and PARG recombinant proteins
• Poly(ADP-ribose) biochemistry
• DNA repair assays
• Cell death, differentiation and proliferation studies
• Tumorigenesis assays, xenografts
Unique selling points :
• Extensive and worldwide expertise in cellular response to DNA damage and PARPs
biology
• Pioneer in the development of human cell lines and mouse models deficient in PARP
family members (Parp-1-/-, Parp-2-/-, Parp-3-/- and Parp-9-/- mice as well as combined
mutants)
• Production of highly pure PARPs and PARG enzymes for biochemical, structural and
pharmacological analyses
• Driving force in continuously increasing number of stimulating and fruitful collaborations
• Co-funder of the Labex MEDALIS «Drug Discovery Center»: access to drug discovery
screening platform and medicinal chemistry optimization processs
25
Poly(ADP-ribosyl)ation
and genome integrity
Françoise DANTZER
Valérie SCHREIBER
Project / Expertise
PARP-3, a key actor in double-strand break repair and mitosis
Results
PARP3 :
• is involved in the repair of double-strand breaks
(DSB) and controls telomere segregation
and microtubule dynamics for faithfull mitosis.
Boehler et al (2011) PNAS, 108:2783-2788.
• influences the DSB repair pathway choice and
inhibits resection to drive repair towards the
non-homologous end-joining route.
Beck et al (2014) Nucleic Acids Res. 42: 5616-5632.
Perspectives
• to decipher the importance of PARP3 in stem cell
fate and tumorigenesis
• to define the molecular properties of PARP3 in
DSB repair
Critical role of PARG to prevent the detrimental accumulation of PAR following
genotoxic insult
Results
PARG:
• ifacilitates repair of radioinduced DNA damages, and reduced radiotoxicity
Amé et al (2009) J Cell Biol 122, 1990-2002
• a novel modulator of replicative stress, to
facilitate recovery from prolonged replication stress by preventing the detrimental accumulation of PAR and DSB
Illuzzi et al (2014) Nucleic Acids Res 42,7776-92.
Perspectives
• targeting PARG to potentiate cytotoxicity of genotoxic and anti-replicative drugs ?
•d
eciphering how PARG activity is tightly regulated in vivo
26
Epigenetic control of
normal and pathological
hematopoiesis
Estelle Duprez
Ph.D.
Contact: [email protected]
> Research Center; Town: C
entre de Recherche en
Cancérologie de Marseille (CRCM)
Marseille
> Administrative affiliations: Inserm UMR 1068 - CNRS UMR
7258 - Université Aix-Marseille
> Tech Transfer Office: Inserm Transfert
www.inserm-transfert.fr
Keywords:
• Leukemia
• Epigenetics
• Hematopoietic stem cell
• H3K27me3
Synopsis
We are applying our in vitro and in vivo epigenetic expertise to understand and characterize malignant
hematopoiesis.
Abstract
Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adult patient, characterized
by its high heterogeneity in terms of biology and clinical outcome. Our team aims to characterize epigenetic
and transcription factors and assess their role in the development of leukemia. Using epigenetic profiling
on patients samples, we recently discovered a new epigenetic alteration that affects CN-AML and impacts
on prognosis. We demonstrated that a specific locus, the HIST1 cluster, was targeted by epigenetic events
that leads to high H3K27me3 level and predicted a good prognosis independently of the already known
biomarkers. We will further characterize this new epigenetic abnormality by developing its clinical interest
in AML and other pathology. We will also explore the underlying mechanisms that lead to this epigenetic
deregulation. We hope that our work will allow the discovery of new biomarkers and therapeutic targets.
Selected references
Grants
• Inserm Transfert (130 k€) EPILAM
• ITMO-cancer, appel d’offre épigénétique (146,3 k€) TransEpiLe
• IncaPLBIO, (230 k€)
Major publications over the past four years
• Andrea Kühnl, Peter Valk, Mathijs Sanders, Robert Hills, Ken Mills, Rosemary E Gale, Martin Kaiser, Richard Dillon, Melanie Joannides, Adam Ivey,
Amanda Gilkes, Torsten Haferlach, Susanne Schnittger, Estelle Duprez,
David Linch, Ruud Delwel, Bob Löwenberg, Claudia Baldus, Ellen Solomon,
Alan Burnett, and David Grimwade. Down-regulation of the Wnt inhibitor CXXC5 predicts a better prognosis in acute myeloid leukemia. Blood,
7;125(19):2985-94 (2015)
• Navarro, JM, Touzard, A, Pradel, L, Loosveld, M, Koubi, M, Fenouil, R, Le
Noir, S, Ahmad Maqboo, M, Morgado, E,, Gregoire, C, Jaeger, S, Mamessier,
E, Pignon, C, Hacein-Bey, S, Malissen, B Gut,M Gut,I, Dombret, H, Macintyre,
E, Howes, S, Thrasher, A, Ifrah, N, Payet-Bornet, D, Duprez, E*, Andrau, JC*,
Asnafi, V*, and Nadel,B*. Site-& allele-specific de-silencing of polycomb repressive activity by insertional oncogenesis: a new recurrent mechanism of
TAL1 activation in T-ALL. Nat Commun, 23;6:6094.(2015). * Equal contribution.
• Tiberi, G, Pekowska, A, Oudin, C, Ivey, A, Prebet, T, Koubi, M, Lembo, F,
Mozziconacci, MJ, Bidaut, G, Autret, A, Chabannon, C, Grimwade, D, Vey, N,
Spicuglia, S, Calmels, B, Duprez, E. PcG methylation of the HIST1 cluster
defines an epigenetic marker of Acute Myeloid Leukemia Leukemia, Epub
2014 Dec 8 29(5):1202-6 (2015)
• Spicuglia S, Vincent-Fabert C, Benoukraf T, Tiberi G, Saurin AJ, ZacariasCabeza J, Grimwade D, Mills K, Calmels B, Bertucci F, Sieweke M, Ferrier
P, Duprez E. Characterization of genome-wide PLZF/RARA target genes.
PLoS ONE ; 6 (9):e24176 (2011).
Patents
• EP14305672.9.NEW BIOMARKER FOR AML
27
Epigenetic control of
normal and pathological
hematopoiesis
Estelle Duprez
Business Development Opportunities
Objectives:
• Characterization of PcG recruitment to chromatin
• Identify new molecular targets in AML
• Development of a new epigenetic marker in AML
Tools:
• Patient samples
• Mouse models
• Chromatin immunoprecipitation
• Bioinformatics
Unique selling points :
• Discovery of epigenetic markers
• Unique expertise in genomewide technologies applied to patient samples
• Developing epigenetic approaches with potential in clinic
28
Epigenetic control of
normal and pathological
hematopoiesis
Estelle Duprez
Project / Expertise
IMPACT OF A NEW EPIGENETIC BIOMARKER in AML
Results
• (A) Epigenetic profiling reveals a specific
H3K27me3 signature in AML
• (B) High HIST1 H3K27me3 level correlates
to good prognosis
• (C) High HIST1 H3K27me3 is an independent prognosis marker in AML
Perspectives
Extend the impact of the epigenetic signature:
• Other malignancies
• Treatment response
29
Epigenetic and
Alternative Splicing
Reini Fernandez de Luco
Ph.D.
Contact: [email protected]
> Research Center; Town: Institut de Génétique Humaine (IGH)
Montpellier
> Administrative affiliations: CNRS UPR 1142
> Tech Transfer Office: aXLR
www.axlr.com
Keywords:
• Alternative splicing
• Epigenetics
• Non-coding RNA
• Long non-coding RNA
• EMT
Synopsis
Our group aims at the better understanding of the role of epigenetics and long non-coding RNAs in the
onset and maintenance of tissue-specific splicing programs using as a cell redifferentiation model system
the epithelial-to-mesenchymal transition (EMT).
Abstract
Alternative splicing is one of the most general and important biological processes in the eukaryotic cell. It
affects more than 90% of human genes, it is essential for protein diversity and any misregulation of the highly
tissue-specific alternative splicing programs can lead to disease, such as cancer. However the mechanisms
of cell-specific alternative splicing regulation are still largely unknown. We have shown that non-coding
RNAs and histone marks can talk to the splicing machinery via recruitment of chromatin/splicing-adaptor
complexes. The can play a role in the onset and maintenance of tissue-specific splicing programs using as
a cell redifferentiation model system the EMT. For that purpose we will use chromatin immunoprecipitation
(ChIP) and genome-wide strand-specific RT and ChIP deep-sequencing to depict the molecular mechanisms
of regulation of tissue-specific alternative splicing.
Selected references
Grants
• ATIP / AVENIR – with the support of the ARC
• Inserm Plan Cancer
• Epigenesys Network of Excellence in Epigenetics and Systems Biology
(FP7-RISE1)
• Marie Curie Career Integration Grant (FP7-CIG)
Major publications over the past four years
• Gonzalez I, Munita R, Agirre E, Dittmer TA, Gysling K, Misteli T and Luco
RF.* A long non-coding RNA regulates alternative splicing via establishment
of a splicing-specific chromatin signature. Nature Structural Molecular Biology 2015, 22(5):370-6.
• Luco RF.* The Non-Coding Genome: a universe in expansion for fine-tuning the coding world. Genome Biology 2013, 14(11):314.
• Luco RF* and Misteli T. More than a splicing code: Integrating the role
of RNA, chromatin and non-coding RNA in alternative splicing regulation.
Current Opinion in Genetics and Development 2011, 21:1-7.
• Luco RF, Allo M, Schor IE, Kornblihtt AR, Misteli T. Epigenetics in alternative pre-mRNA splicing. Cell 2011, 144 (1): 16-26.
• Luco RF, Pan Q, Tominaga K, Blencowe BJ, Pereira-Smith O, Misteli T.
Regulation of alternative splicing by histone modifications. Science 2010,
327(5968):996-1000
30
Epigenetic and
Alternative Splicing
Reini Fernandez de Luco
Business Development Opportunities
Objectives:
• To uncover the role of histone marks and long non-coding RNAs in the regulation of
EMT-specific alternative splicing programs.
• To modulate splicing of key EMT events by modulating chromatin and/or lncRNAs
expression levels.
• To impair EMT progression and malignancy by using the newly identified splicing
regulators.
Tools:
• High-throughput sequencing: ChIP-seq and strand-specific RNA sequencing
• CRISPR/Cas9 system for epigenetic editing and knock out of lncRNAs
• E MT induction of human epithelial MCF10a-Snail-ER cells
(EMT: Epithelial-to-mesenchymal transition – involved in cancer and metastasis)
Unique selling points:
• Unique expertise in a young field in expansion that studies the interplay between
chromatin and alternative splicing regulation.
• Innovative approaches to address the direct role of histone marks in splicing regulation
by adapting the CRISPR/Cas9 system to edit the epigenome.
• Interdisciplinary project combining genome-wide/computational approaches with genespecific analysis to depict novel mechanisms of splicing regulation.
• Use of a dynamic and physiologically relevant cell reprogramming system, the EMT, to
discover novel tools to revert disease-specific splicing events.
• Identification of chromatin signatures as potential biomarkers for detection of early
stages of metastasis.
• Development of lncRNAs as a more specific and target-orientated therapeutic strategy
(RaNA Therapeutics and Isis Pharmaceuticals are US companies already targeting
diseases using this strategy – in clinical trial for myotonic muscular dystrophy).
31
Epigenetic and
Alternative Splicing
Reini Fernandez de Luco
Project / Expertise
Chromatin cross-talks to the splicing machinery via chromatin-adaptor complexes
Results
• Alternatively spliced exons are enriched in specific subsets of histone marks. These marks play
a direct role in splicing regulation by inducing recruitment of specific splicing regulators to the premRNA via protein-protein interaction with chromatin-binding proteins that act as adaptors.
Perspectives
• To predict alternative splicing patterns based
on the subset of histone marks enriched along an
exon and to modulate the final splicing outcome by
modulating these characteristic chromatin signatures.
Chromatin cross-talks to the splicing machinery via chromatin-adaptor complexes
Results
• The expression of a lncRNA within FGFR2
locus triggers recruitment of chromatin
complexes, amongst Polycomb, that create
the chromatin signature necessary for inclusion of the epithelial-specific splicing isoform. In the absence of the lncRNA, there
is a chromatin remodeling that favors inclusion of the mesenchymal isoform.
Perspectives
• To use lncRNAs to induce or revert a specific splicing event as a novel therapeutic
strategy to treat splicing-specific diseases.
32
Deciphering functional activity of
TLX homeodomain oncogenes in
T-cell Acute Leukemia (T-ALL):
Epigenetic analysis
Pierre Ferrier
MD, PhD / Inserm Research
Director / Team Leader
Contact: [email protected]
> Research Center; Town: C
entre d’Immunologie de MarseilleLuminy (CIML), Marseilles, France
> Administrative affiliations: Inserm U1104 - CNRS
UMR7280 - Université Aix
Marseille
> Tech Transfer Office: Inserm Transfert
www.inserm-transfert.fr
Keywords:
• Epigenetics
• Lymphoid cell differentiation
• Gene expression and Recombination
• Leukemia
Synopsis
http://www.ciml.univ-mrs.fr/science/lab-pierre-ferrier/home
Abstract
We investigate the molecular mechanisms involved in the control of differentiation events during lymphocyte
development including antigen receptor gene expression and recombination. One approach is to characterize
cis-regulatory elements and bound factors at lymphoid gene specific loci and to infer their impact on chromatin
structure using molecular biology, high-throughput genomics (microarrays, ChIP-Chip, ChIP-seq, RNA-seq,
MeDIP, FAIRE) and bio-informatics; as well as transgenic mouse and gene targeting (knockout/knockin)
technologies. Mutant animals are being used to study precursor-product relationships along lymphoid cell
developmental pathways, assisted and implemented by mathematical simulation [in collaboration with the
team ‘Non-Linear Dynamics’ at the Center for Theoretical Physics (CPT), Luminy Campus]. We likewise
analyze epigenetic events linked to leukemo/lymphomagenesis. Hence, we aim to define the (epi)genetic
networks sustaining lymphoid cell ontogenesis and oncogenesis.
Selected references
Grants
• ANR Blanc International 2014-16: ‘Epigenetics and alternative splicing:
role in immune T cell differentiation and leukemogenesis’ [P. Ferrier, coordinateur - Collaboration: M. Carmo-Fonseca, IMM Lisbonne (Portugal)]
• Inserm ITMO Aviesan Plan Cancer, Epigénétique & Cancer (2014-16) &
INCa ‘Biologie & Sciences du Cancer (2014-16) Deciphering the functional
activity of TLX oncoproteins in T-ALL: a stride towards differentiation therapy’ [P. Ferrier, coordinateur - Collaboration: I. André-Schmutz & V. Asnafi,
Institut Necker Paris]
Major publications over the past four years
• Long-range control of V(D)J recombination and allelic exclusion: Modeling
views. Outters et al.. Adv Immunol. 128, vol. Long Range Regulation of V(D)
J Recombination. Cornelis Murre, Ed. (In press).
• Transcription-dependent generation of a specialized chromatin structure at the TCRbeta locus. Zacarías-Cabeza et al. J Immunol. 2015 Apr
1;194(7):3432-43
• TLX homeodomain oncogenes mediate T cell maturation arrest in T-ALL
via interaction with ETS1 and suppression of TCRalpha gene expression.
Dadi et al. Cancer Cell. 2012 Apr 17;21(4):563-76.
• H3K4 tri-methylation provides an epigenetic signature of active enhancers. Pekowska et al. EMBO J. 2011 Aug 16;30(20):4198-210.
• Transcription initiation platforms and GTF recruitment at tissue-specific enhancers and promoters. Koch et al. Nat Struct Mol Biol. 2011 Jul
17;18(8):956-63.
• A unique H3K4me2 profile marks tissue-specific gene regulation. Pekowska et al. Genome Res. 2010 Nov;20(11):1493-502. doi: 10.1101/
gr.109389.110. Epub 2010 Sep 14. PMID: 20841431
• TCR beta allelic exclusion in dynamical models of V(D)J recombination based on allele independence. Farcot et al. J Immunol. 2010 Aug
1;185(3):1622-32.
33
Systems biology of cell
fate decisions in normal
and tumor cells
Hinrich Gronemeyer
Ph.D.
Contact: hg @ igbmc.fr
(PA: [email protected])
> Town: Strasbourg
> Administrative affiliations: Université de Strasbourg EA3430
> Tech Transfer Office: Conectus
www.conectus.fr
Keywords:
• Gene regulatory programs for retinoic acid receptorinduced cell differentiation and stepwise tumorigenic
transformation of human primary cells
• Mechanism of selective tumor cell killing by the TRAIL
pathway
• Genesis and function of non-coding RNAs
Synopsis
We perform integrative genome-wide analyses (signalling, transcriptome, epigenome, chromatin architecture),
and develop the required technologies and bioinformatics tools, to (i) understand (patho)physiological cell
fate acquisitions and (ii) discover novel regulatory principles.
Abstract
We are deciphering the temporal evolution of gene networks that are involved in physiological (cell
differentiation, lineages progression) and pathological (tumorigenesis models) cell fates. We generate a
comprehensive view of the regulation of corresponding interconnected networks of genes. For this we have
developed technologies (LinDA, TARDIS) and bioinformatics tools (big data QC, normalization and analysis).
Our studies of the tumor susceptibility loci-rich RAM region led to the discovery of novel regulatory natural
double stranded RNAs (ndsRNAs). We will define the biogenesis and biological function of ndsRNAs and
their role in cell fate acquisition, generating an entirely novel field of research and possibly completely novel
types of biomarkers and targets. Our studies of the tumor-selectivity of, and resistance to TRAIL will lead to
new cancer-therapeutic tools.
Selected references
Grants
• ITMO Cancer – Aviesan // Ligue Labelisée //ANR // World-wide Cancer
Research (AICR)
Major publications over the past four years
• Portal MM et al (2015) TARDIS, a Targeted RNA Directional Sequencing
method for rare RNA discovery. Nat Protoc, in press [IF 13.5] (patent application)
• Chaligné R et al (2015) The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer. Genome Res 25, 488 [IF
15.6]
• Portal M et al (2015) Human cells contain natural double-stranded RNAs
with potential regulatory functions. Nat Struct Mol Biol 22, 89 [IF 13.3] 3x
recommended by F1000Prime; 2 patent applications
• Shankaranarayanan P et al (2012) Single-tube linear DNA amplification
(LinDA) for genome-wide studies using a few thousand cells. Nat Protoc 7,
328 [IF 13.5] (patented)
• Mendoza-Parra MA et al (2011) Dissecting the retinoic acid-induced differentiation of F9 embryonal carcinoma cells through integrative genomics.
Mol Sys Biol 7, 538 [IF 12.1].
• Shankaranarayanan, P et al (2011) Single-tube linear DNA amplification
(LinDA) for robust ChIP-seq. Nature Methods 8, 565 [IF 32.1] (patented)
• Ceschin DG et al (2011) Methylation specifies distinct estrogen-induced
binding site repertoires of CBP to chromatin. Genes & Dev 25, 1132 [IF
12.3]
Patents & IP
• 2014 Method of capturing and identifying novel RNAs (EP14306648)
• 2014 Method of sequencing and identifying RNAs (EP14305822)
• Method and system for processing data for evaluating a quality level of a
dataset (WO/2014/083018) : National phases EP, US
• Linear DNA amplification (WO/2012/150317) : National phases EP, US
• Software and database registered in the Agency for the Protection of
Programs (APP)
34
Systems biology of cell
fate decisions in normal
and tumor cells
Hinrich GRONEMEYER
Business Development Opportunities
NGS QC GENERATOR
• Patent application WO/2014/083018
- priority date : November 28th 2012
- national phases EP, US
• Software and database registered in the Agency for the Protection of Programs (APP)
• Seeking partners for licensing or services
• Actively looking for an entrepreneur to exploit the technologies, bioinformatics tools and
know-how through the creation of a start-up : QC GENOMICS
LinDA
• Patent application WO2012150317
- priority date : May 11th 2011
- National phases EP, US
• Seeking partners for licensing or services
• Actively looking for an entrepreneur to exploit the technologies, bioinformatics tools and
know-how through the creation of a start-up : QC GENOMICS
TARDIS
• Patent application PCT/EP2015/062179
- priority date : May 30th 2014
• Seeking partners for licensing
ndsRNA
• Patent application EP14306648
- priority date : October 16th 2014
• Seeking partners for the co-conception of a SATT Conectus Investment program aiming
at the maturation of the ndsRNA capture technology
• Seeking partners for licensing
35
Systems biology of cell
fate decisions in normal
and tumor cells
Hinrich GRONEMEYER
Project / Expertise
QC certification system for genome-wide studies and associated database
• Bioinformatics tool generating both
global and local numerically defined
quality control (QC) parameters for
genome-wide NGS profiling data
sets.
• This QC system is applicable to all
NGS-based profiling and to certification process of antibodies dedicated to genome-wide studies
• First quantifiable measurement for
the quality of sequencing datasets
(ChIP-seq, HiC and related) obtained by massive parallel sequencing
and the quality of the reagents used
for the profiling
• Searchable databases (NGS-QC
for ChIP-seq, etc. & LOGIQA for
HiC and other long-range chromatin
interactions) comprising a 2-dimensional representation of the global
QC parameters
• This approach allows:
- The attribution of a quality label to
the profiling
- The determination of the optimal
sequencing depth
-
The determination of the best
method to implement for a given
sample
- First QC of antibodies dedicated
to genome-wide studies based on
quantitative descriptors
• Possibility to give insights for the
improvement of the quality of NGS
data obtained with a given antibody
• www.ngs-qc.org for further information
36
Systems biology of cell
fate decisions in normal
and tumor cells
Hinrich GRONEMEYER
Project / Expertise
High-throughput sequencing of picogram amounts of DNA
• Versatile and robust DNA amplification method, for ChIP-seq
and re-ChIP-seq with picogram
DNA amounts
• Single-tube RNA polymerasebased linear DNA amplification
technology which facilitates global chromatin analyses with very
limited cell populations, such as
stem or cancer initiating cells.
• Consecutive steps are performed in the same tube by sequential addition of reagents, thus
eliminating the need for column
purification and minimizing the
risk of sample losses particularly
at early steps.
• Unique GC bias-free DNA amplification technology (PCR-free
procedure)
• The single tube design of LinDA
is ideal for handling ultra-small
amounts of DNA (>30pg) and is
compatible with automation
• The actual hands-on working
time is less than 6h with one
overnight reaction
• Can be coupled to a great
number of global profiling technologies
• Allows NGS data pre-processing thanks to the tool TrimLinDA
• Technology being further developed to improve sensitivity,
versatility (bar coding for large
sample sizes) and simplicity.
37
Systems biology of cell
fate decisions in normal
and tumor cells
Hinrich GRONEMEYER
Project / Expertise
TARgeted RNA DIrectional Sequencing
method for rare RNA discovery
• Novel technology for comprehensive target discovery
by RNA capture followed by strand-specific RNA-seq
• Enables the robust identification and reconstruction
of any kind of known or unknown RNA species, independently of the length, level of expression, poly-A presence or function.
• Cheapest and at the same time only comprehensive
RNA-seq technology
• Based on the direct hybridization of DNA traps generated from any DNA library of interest (i.e Bacterial Artificial
Chromosomes (BAC) covering a region of interest), with
either the natural small RNA fraction or the entire RNA
repertoire.
• Workflow comprising 5 main steps:
1) BAC selection & production of biotinylated traps
2) RNA sample purification
3) targeted RNA capture,
4) Strand-specific RNA-seq library preparation,
5) RNA-seq data analysis.
• Experimental workflow is performed within 10 days in a
typical research lab setting.
• Validated with the discovery and identification of ndsRNA
Capture, identification and use of ndsRNA
• ndsRNA: recent and original discovery of a novel
class of non-coding RNAs with regulatory potential
for major cell functions
• Development of a method for the specific capture
and identification of ndsRNAs (under development)
• Potential use of ndsRNAs/patterns as a novel type
of biomarkers
• Potential ndsRNA-based therapeutics interfering
with essential cell physiological functions, such as
proliferation and epigenetics
• ndsRNAs are critically involved in mitosis
• ndsRNAs interact with different regulatory, including
mitotic complex and epigenetic factors/machineries
Perspectives
• ndsRNAs as biomarkers
• ndsRNA-based therapeutics
• ndsRNAs constitute a novel field of research with
enormous innovative potential for translational research
38
Regulation of gene by
microRNAs in Cancer
and Development
Christophe GROSSET
Ph.D.
Contact: [email protected]
> Research Center; Town: G
roupe de Recherche pour l’Etude
du Foie (GREF), Bordeaux
> Administrative affiliations: Inserm U1053 - Université de
Bordeaux
> Tech Transfer Office: Aquitaine Science Transfert® is the
technology transfer office in charge of our laboratory. Created in
July 2012 by the French government, the aims of this TTO are
mainly to boost the academic research results and to improve
the efficiency of technology transfer to companies and to create
economic value. Two European patents have been deposited last
July with Christophe Grosset’s team in order to protect microRNAs
with prognostic and therapeutic properties in liver cancer.
http://ast-innovations.com/
Keywords:
• Liver cancer: Hepatocellular carcinoma, hepatoblastoma
• Paediatric and adult patients
• MicroRNAs
• Oncogenes: Glypican-3, Beta-catenin
• Clinical biomarkers
• miRNA-replacement therapy
Synopsis
My research aims at identifying oncogene-regulating microRNAs that constitute clinical biomarkers (for
diagnosis, prognosis or treatment response) and/or therapeutic drugs in adult and paediatric liver cancers.
Abstract
My research is focused on the study of the molecular mechanisms involved in two types of liver cancer:
hepatocellular carcinoma and hepatoblastoma. My expertise is about the post-transcriptional regulation of
oncogenes (Glypican-3, β-catenin …) by microRNAs and their role in liver carcinogenesis. My research
strategy comprises in cellulo functional screening of microRNA libraries, validation of microRNA candidates,
assessment of their relevance in patients’ tissues and the study of their biological functions using cell-based
tests and animal models (chick chorioallantoic membrane, mouse). My team identified several microRNAs
targeting key oncogenes in liver cancer, presenting antitumoral properties in vitro in association or not with
clinical drugs and constituting reliable clinical biomarkers. My future work aims at identifying new microRNAs
for the treatment and the clinical management of adult and paediatric patients with liver malignancies.
Selected references
Grants
• Cancéropôle Grand Sud-Ouest
• INCa PLBIO 2012
• INCa TRANSLA 2013
• FRM BIOINFO 2013
• Ligue Nationale contre le Cancer
Major publications over the past four years
• Jalvy-Delvaille, S., et al. (2012). Molecular basis of differential target regulation by miR-96 and miR-182: the Glypican-3 as a model. Nucleic Acids
Res 40, 1356-1365.
• Maurel, M., et al. (2013a). MicroRNA-1291-mediated silencing of IRE1alpha enhances Glypican-3 expression. RNA 19, 778-788.
• Maurel, M., et al. (2013b). A functional screening identifies five micrornas
controlling glypican-3: role of mir-1271 down-regulation in hepatocellular
carcinoma. Hepatology 57, 195-204.
Patents
• “Use of catenin- beta 1-targeting microRNAs for treating liver cancer”- EP
patent filling
• “Use of glypican-3-targeting microRNAs for treating liver cancer” - EP
patent filling
39
Regulation of gene by
microRNAs in Cancer
and Development
Christophe GROSSET
Business Development Opportunities
Objectives:
• Identifying miRNAs targeting pathways and genes involved in hepatocarcinogenesis
• Evaluating the therapeutic potential of these miRNAs in liver cancer (hepatocellular
carcinoma and hepatoblastoma)
• Identifying miRNAs as biomarkers for prognosis and diagnosis in liver cancer
• Determining the differential miRNAs/genes expression in tumoral versus non tumoral
tissue in patients
Tools:
• Innovative functional approach to study post-transcriptional regulations (FunREG)
• Innovative screening system (Dual Fluorescence-FunREG)
• Panels of adult and pediatric tumors and adjacent non-tumoral livers
• Chick chorioallantoic membrane model
Unique selling points:
• The Dual Fluorescence-FunREG screening system. Screening of libraries of miRNAs,
shRNAs, sgRNA, chemical components…
• The chick chorioallantoic membrane model
• MicroRNAs with antitumoral properties in liver cancer (potentially in other types of
cancer)
• MicroRNAs for diagnosis and prognosis
40
Regulation of gene by
microRNAs in Cancer
and Development
Christophe GROSSET
Project / Expertise
Use of Glypican-3-targeting microRNAs for treating liver cancer
Results
• Identification of 5 Glypican-3-regulating miRNAs with
antitumoral properties in hepatocellular carcinoma (HCC)
and in hepatoblastoma (HB).
• These miRNAs are down-regulated in tumors and in some
case, they act as prognostic biomarkers.
Perspectives
• Preclinical studies in mice.
• Development of innovative miRNA-replacement therapies
in association with Sorafenib or Cisplatin.
Use of b-catenin 1-targeting microRNAs for treating liver cancer
Results
• Identification of 5 b-catenin-regulating miRNAs with
antitumoral properties in hepatoblastoma (HB).
• These miRNAs are down-regulated in tumors and in
some case, they act as prognostic biomarkers.
Perspectives
• Preclinical studies in chick chorioallantoic membrane.
• Development of innovative miRNA-replacement therapies in association with Cisplatin.
41
Impact of hypoxia and
microenvironment in tumor
progression and response to
treatment. Translational approaches
and epidemiology
Dominique GUENOT
Ph.D.
Contact: [email protected]
> Center, town: Strasbourg
> Administrative affiliations: Université de Strasbourg EA3430
> Tech Transfer Office: Conectus
www.conectus.fr
Keywords:
• Preclinical development
• Hypoxia
• Resistance
• Xenografts
• Tumor banking
• Molecular biology, genomics, transcriptomics
Synopsis
The team composition with researchers, clinicians, scientists and doctoral students in medical training as well
as collaborations with established hospital services, represent a major strength of this team for achieving a
preclinical translational research Cancer.
Abstract
The goal of our project is to specify the molecular mechanisms by which hypoxia, according to its severity and
in close interaction with microenvironment, can dependently or independently of HIFs, promote metastatic
spread and resistance to cancer therapies (chemotherapy, radiotherapy ...). Understanding these mechanisms
will lead to the identification of new markers prognostic of dissemination and predictive of response to
treatment. Demonstration of the functional role of such markers will optimize current treatments and develop
alternative therapeutic strategies, validated by clinical trials. Our expertise relies on the development of
research projects that benefit from both fundamental and applied research in order to establish a continuum
between the bedside and the research laboratory.
Selected references
Grants
• Idex Attractivity project
• Ligue contre le cancer
• Projet de Recherche et Développement Structurant des Pôles de Compétitivité (PSPC) : Imodi
• Alsace contre le cancer
• Roche : research in personalized medicine
• INCa
Major publications over the past four years
• Neuville A, et al, Human Pathology, 2011
• Guérin G et al, Molecular Medicine, 2012
• Marisa L, et al, Plos Medicine, 2013
• Schmitt C, et al, Bio Med Chem, 2013
• Prim N, et al, Eur Respir Rev, 2014
• Romain B, et al, Molecular cancer, 2014
• Weingertner N, Pathology, 2015
42
Impact of hypoxia and
microenvironment in tumor
progression and response to
treatment. Translational approaches
and epidemiology
Dominique GUENOT
Business Development Opportunities
Objectives:
• Impact of hypoxia on dissemination and resistance processes
• Impact of chemokine axis on dissemination process
• Develop translational therapeutic strategies based on drug combinations
Tools:
• Proteomics / metabolomics / genomics – NGS)
• Radiobiology (cells and small animal)
• Xenografts in nude mice
• Biobank and biological resource center with important tumor bank (numerous solid
cancers (cerebral, lung, colon, VADS carcinomas, lymphomas, osteosarcomas)
Unique selling points:
• Development of translational research within a pole of fundamental cancer teams
• Important collection of solid tumors
• Epidemiologist and biostatisticians as team members to develop early phase clinical
trials
• Close interaction between researchers and clinicians (oncologists, surgeons, anatomopathologists)
43
Impact of hypoxia and
microenvironment in tumor
progression and response to
treatment. Translational approaches
and epidemiology
Dominique GUENOT
Project / Expertise
CXCLx/CXCRy/CXCRz axis in human colon cancer
Results
In human colon carcinomas:
• Loss of CXCLx expression in part of adenomas
• No more CXCLx expression
• CXCLx promoter acetylation rather than methylation
in APC mutated mice, HDAC inhibitor Valproate :
• Diminishes number of spontaneously developped intestinal
tumors
• Reexpressed CXCLx in tumor intestinal cells
Perspectives
• Identify enzymes and their targets that are involved in the regulation of methylation and acetylation of CXCLx promoter
• Evaluate if loss of CXCLx expression participates to tumor cell
dissemination
CXCRs membranous expression and hypoxia
Results
• Increased expression according to the carcinoma clinical stage
• Hypoxia-increased expression of CXCRy via the expression of
HIFs
• CXCRy is maintained at the membrane up to 48 hours after
return to normoxia
• No impact of hypoxia on CXCRz expression
Perspectives
• Receptor expressions in human colon carcinoma - prognostic
value
• Role of CXCRy and / or CXCRz in metastasis
• Translational development: Inhibit metastatic process via HIFs
and CXCRy/CXCRz inhibitors
44
PU.1 transcription factor
in epigenetic and splicing
regulation
Christel Guillouf
Ph.D.
Contact: [email protected]
> Center, town: Gustave Roussy Institute, Villejuif
> Administrative affiliations: Inserm-U1170 - CNRS
> Tech Transfer Office: Inserm Transfert
www.inserm-transfert.fr
Keywords:
• PU.1 transcription factor
• Alternative Splicing
• Epigenetic regulation
• Hematopoeisis
• Leukemia
Synopsis
Our work aims at deciphering the impact of transcription factors on chromatin structure, transcription and
splicing in leukemia initiation and progression
Abstract
Acute Myeloid Leukemias (AMLs) are due to the progressive accumulation of mutations in genes coding for
proteins participating to signalling networks, for transcription factors (TFs) and for splicing and epigenetic
regulators, leading to deep changes in global gene expression. Genetic alteration of a hematopoietic TF
determines AML specificity by blocking the differentiation process of a specific lineage. We aim to describe
the molecular mechanisms through which TF drives transformation. Because we know that TFs interact
physically with epigenetic and splicing factors and that gene expression results from the coordinated control
of these three types of factors, we hypothesized that TFs act by modifying the specificity and activity of
epigenetic and splicing regulators in leukemia. To validate our hypothesis, we characterize the mechanisms
by which the PU.1 TF, whose a fine-tuning activity is involved in hematopoietic differentiation and leukemia,
modifies gene expression in normal and leukemic cells.
Selected references
Grants
• ITMO-cancer, appel d’offre épigénétique TransEpiLe 2013
• IncaPLBIO 2014
• Ligue Nationale contre le Cancer
Fondation de France
Major publications over the past four years
• Ridinger-Saison et al., 2013, Epigenetic silencing of Bim transcription by
Spi-1/PU.1 promotes apoptosis resistance in leukaemia. Cell Death and
Differentiation, 20, 1268-78
• Boeva et al., Nebula-a web server for advanced ChIP-seq data analysis.
Bioinformatics, 2012, 28, 2517-9.
• Ridinger-Saison et al., 2012, Spi-1/PU.1 activates transcription through
clustered DNA occupancy in erythroleukemia. Nucleic Acid Research, 140,
8927-41.
• Rimmelé et al., 2010, Spi-1/PU.1 oncogene accelerates DNA replication
fork elongation and promotes genetic instability in the absence of DNA
breakage. Cancer Res., 70, 6757-66.
45
PU.1 transcription factor
in epigenetic and splicing
regulation
Christel Guillouf
Business Development Opportunities
Objectives:
• To define whether high PU.1 expression controls gene expression by modifying
epigenetic marks and regulators. We focus, in particular, on the interplay between PU.1
TF and PcG complex.
• To characterize how PU.1 modify alternative splicing, ie dependent on DNA or RNA
binding or through competitive activity on proteins.
• To define how PU.1 interconnect alternative splicing, epigenetic regulation and
transcriptional targets in leukemia
Tools:
• Murine model of leukemia: PU.1 transgenic mice
• Cells with graded PU.1 expression
• ChiP-seq
• RNA-seq
• CLiP-seq
Unique selling points:
• Innovative approaches to address the role of PU.1 in RNA binding, Clip-seq
• Unique expertise in PU.1 transcription factor
• Study combining genome-wide strategy with gene expression analysis in in vivo and in
cellulo model of leukemia
• Use of a well-defined multistep leukemic model
46
PU.1 transcription factor
in epigenetic and splicing
regulation
Christel Guillouf
Project / Expertise
Interplay between PU.1 and PcG complex and its role in leukemogenesis
Results
PU.1 represses apoptosis and the pro-apoptotic Bim
gene through binding to Bim promoter. PU.1 interacts
with PRC2 complex also bound upstream in the Bim
promoter and increases the H3K27me3 mark at this
gene, leading to the repression of RNA transcription.
Perspectives
We will study the functional relationship between PU.1
and PRC2 by analysing the two following hypotheses:
PU.1 recruits or modulates the activity of PRC2 at the
Bim promoter and at others targets that need to be
identify.
Interconnection between PU.1, alternative splicing, epigenetic control and transcriptional targets
Results
We know that PU.1 interacts with splicing
factors, epigenetic factors, binds to DNA
and RNA and modifies alternative splicing.
Perspectives
We will use genome wide approaches(see
the figure) to characterize how PU.1
regulates all these steps of gene expression regulation and define specific targets
involved in leukemogenesis. For that, we
will compare leukemic cells overexpressing PU.1 and normal cells.
47
Epigenome deregulation
and cancer : mechanisms
and biomarkers
Zdenko HERCEG
Ph.D, Group Head, Department Head
Contact: [email protected]
> Center, town: International Agency for Research on Cancer
(IARC) Lyon, France
> Administrative affiliations: International Agency for Research
on Cancer (IARC) – World Health
Organisation (WHO)
> Tech Transfer Office: World Health Organisation (WHO)
Keywords:
• Epigenetics
• Cancer
• Mechanisms of carcinogenesis
• Biomarkers
• Environment
Synopsis
Our laboratory exploits new concepts in cancer epigenetics and recent technological advances in epigenomics
in conducting both mechanistic studies and epigenetic profiling, aiming to enhance our understanding of
mechanisms of carcinogenesis and cancer causation and to discover and validate new epigenetic biomarkers.
Abstract
Improving the knowledge of mechanisms of cancer development related to environmental factors provides a
foundation for studies of cancer etiology, therapy and prevention. Our group leads a multi-faceted research
programme on epigenetic mechanisms of carcinogenesis and identification and validation of epigeneticbased biomarkers of exposure and cancer risk that enables the testing of new etiological hypotheses and
provides the basis for preventive and treatment strategies. Our studies are multidisciplinary, and extensive
collaborations have been developed with laboratory scientists, epidemiologists, and biostatisticians from
around the world. Our mechanistic studies are focused on functionally important epigenetic changes and
molecular pathways altered in response to cancer risk agents using in vitro models and state-of-the-art
approaches. List of Published Work in MyBibliography:
https://scholar.google.com/citations?hl=en&user=T8GCNZkAAAAJ&view_op=list_works
Selected references
Grants
• INCa – Epigenetic precursors of childhood cancer. 2015-18, 576,000 €
• EU FP7 - A randomized phase II study with Metformin in breast cancer.
2014-17, 1,230,320 €
• INCa - Cancer cell identity and gene expression layers. 2014-2017,
469,760 €
• NIH - MicroRNA & Breast Cancer: Functional Characterization.2013-2018,
4,063,604 USD
• EU FP7 - An integrated approach for epigenetic biomarkers of breast
cancer. 2014-17, 1,388,363 €
• INCa – Epigénome et risque de cancer du sein. 2012-15, 650,000 Euros
• EU FP7 - EXPOsOMICS. Co-Is: Z. Herceg 2012-16, 9,000,000 €
• Bill&Melinda Gates Foundation - Identifying biomarkers for aflatoxin exposure. 2013-16,. 2,000,000 USD
Major publications over the past four years
• Vaca-Paniagua F et al Targeted deep DNA methylation analysis of circulating cell-free DNA in plasma using high-throughput semiconductor sequencing. Epigenomics, 2015 in press
• Tapias A et al. Trrap-dependent histone acetylation specifically regulates
cell-cycle gene transcription to control neural progenitor fate decisions. Cell
Stem Cell. 2014 May 1;14(5):632-43.
• Lee HS et. Modulation of DNA methylation states and infant immune
system by dietary supplementation with ω-3 PUFA during pregnancy in an
intervention study. Am J Clin Nutr. 2013 Aug;98(2):480-7.
• Ichim G et al The histone acetyltransferase is targeted for destruction
during cell cycle. Oncogene 2014 Jan 9;33(2):181-92.
Genevois AL et al Dependence receptor TrkC is a putative colon cancer
tumor suppressor. PNAS 2013 ;110(8):3017-22
• Paliwal A et al Aberrant DNA methylation links cancer susceptibility locus
15q25.1 to apoptotic regulation and lung cancer. Cancer Research 2010;
70:2779-2788.
Murr R et al Histone acetylation by Trrap-Tip60 modulates loading of repair proteins and repair of DNA double-strand breaks. Nature Cell Biology
2006; 8:91-99.
48
Epigenome deregulation
and cancer : mechanisms
and biomarkers
Zdenko HERCEG
Business Development Opportunities
Unique selling points:
• ISuccessful in integrating interdisciplinary skills in laboratory-based research, molecular
epidemiology, and bioinformatics into IARC’s unique international research setting
• Development of high-throughput epigenomic methodologies that are applicable to
biobanks associated with population-based cohorts
• Capacity to generate and analyse genome-wide epigenetic data, enabling a switch from
candidate-gene approaches to epigenome-wide characterization
• Successful grant applications to funding agencies and reinforced home Institute’s
mission by training a large number of early career scientists and catalysed new scientific
collaborations
49
Epigenome deregulation
and cancer : mechanisms
and biomarkers
Zdenko HERCEG
Project / Expertise
Results
To study the biological function of epigenetic regulators in
control of cellular processes and tumorigenesis, we have
taken different approaches that allow inducible inactivation
of specific genes in mice and human cancer cell lines. Our
results reveal that histone acetyltransferases may function as
a molecular link between DNA damage signaling, DNA repair
and cell cycle, and illustrate cellular strategy to use the same
basic mechanism involving histone modifying complexes to
regulate and coordinate distinct cellular processes, such as
transcription and DNA repair, and to protect genomic stability.
Perspectives
Advance knowledge of mechanisms
of cancer development involving epigenetic regulationand
underpin studies of cancer etiology, therapy and prevention
Results
• We have established assays for quantitative and highthroughput analysis of DNA and combined these assays with
series of HCC associated with major risk factors and collected from different geographical areas.
• Aberrant methylation of a subset of genes was associated
with tumour progression and etiological risk factors, such as
hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
and alcohol consumption.
• Hypermethylation of an independent panel of genes was
strongly correlated with survival after cancer therapy.
Perspectives
Our findings could be exploited for biomarker discovery in
the clinic and molecular epidemiology studies
50
Functions of lysine
methylation pathways
Eric JULIEN
Ph.D.
Contact: [email protected]
> Research Center; Town: Institut de Recherche en
Cancérologie de Montpellier (IRCM),
Montpellier
> Administrative affiliations: Inserm U1194, Université de
Montpellier
> Tech Transfer Office: aXLR
www.axlr.com
Keywords:
• Tumor solid models
• Epigenetic drugs
• Methylation
• Cell cycle
Synopsis
Our group develops targeted approaches to understand the function of cancer relevant gene families with a
particular focus on epigenetic regulators.
Abstract
Recent genomic sequencing and transcriptome analysis in a vast variety of cancers have revealed that a
large number of chromatin modifiers and chromatin-binding proteins are found mutated or misexpressed in
cancer cells. While known to play key roles in the maintenance of genome structure and functions, these
largely unanticipated mutation and/or misexpression findings could illuminate newly recognized epigenetic
mechanisms potentially central to the genesis of cancer. By developing targeted approaches in both
mammalian and Drosophila genetic models, we are studying functions of key factors in chromatin-associated
signaling pathways, with a particular focus on the family of lysine methyltransferases that regulate nuclear
and epigenetic processes during normal and neoplasic development.
Selected references
Grants
• Plan Cancer-Aviesan-Inserm
Patents
• Ongoing
Major publications over the past four years
• Tardat M., Brustel J., Kirsh O., Lefevbre C., Callanan M., Sardet C. and Julien
E (2010). The Histone H4-K20 methyltransferase PR-Set7 regulates replication origins in mammalian cells. Nature Cell Biology. 11 : 1086-1093.
Selected by faculty 1000 as exceptionnal contribution.
• Brustel J, Tardat M, Kirsh O, Grimaud C and Julien E. (2011) Coupling
mitosis to DNA replication : The emerging role of the lysine methyltransferase PR-Set7 (2011). Trends in Cell Biology. 21 :452-60.6
• Rodier G, Kirsh O, Baraibar M, Houlès T, Lacroix M, Delpech H, Hatchi E,
Arnould S, Severac D, Duboix E, Cramal J, Julien E, Friguet B, Le Cam L &
Sardet C.(2015). Cell reports Apr 14;11(2):220-33.
51
Functions of lysine
methylation pathways
Eric JULIEN
Business Development Opportunities
Objectives:
• Identification of new epigenetic targets for cancer treatment
• Functional characterization of epigenetic drugs for cancer therapy
• Characterization of epigenetic mechanisms in cancer
Tools:
• Cellular and Molecular biology
• Drosophila genetic models
• Bio-computing analysis of ChIP seq/expression data
• access to various clinical samples
Unique selling points :
• Team nationally and internationally recognized for its expertise in histone methylation
and cell cycle regulation
• Original insect and mammalian models for epigenetic studies
• Connections to clinical studies & hospitals
• Strong national and international network of collaborators
• Collaborations with engineering chemistry research labs
• Strong expertise in regulation and functions of lysine methyltransferases
52
Functions of lysine
methylation pathways
Eric JULIEN
Project / Expertise
Replication defects caused by alterations in histone H4-K20 methylation signaling
pathway
Results
• DNA fiber analysis showing defects in replication initiation sites (green) caused by alterations in
H4K20(me) methylation signaling pathways. DNA
fibers are shown in red.
Perspectives
• Identify new epigenetic regulatory mechanisms of
the cell-cycle
• Development of chemical drugs against H4K20me
enzymes to prevent proliferation of cancer cells
Studying cancer-related phenotypes in Drosophila
Results
• Preneoplastic response (hyperplasia) in Drosophila imaginal dics upon loss of a specific epigenetic regulator.
Perspectives
• Genetic screens to identify evolutionary conserved cancer-related genes
• Characterization of new regulatory epigenetic
mechanisms in cell proliferation
53
Epigenetic and Cell
Signaling
Saadi Khochbin
Ph.D.
Contact: khochbin @ujf-grenoble.fr
> Research Center; Town: Institut Albert Bonniot (IAB) Grenoble
> Administrative affiliations: Inserm U823 - Université
Grenoble Alpes
> Tech Transfer Office: Floralis
www.floralis.fr
Keywords:
• Bromodomain
• Acetylation
• Chromatin biology
• Epigenome reprogramming
• Cancer Biomarkers
• Therapeutic targets
• Bioinformatics
Synopsis
Our research on the epigenetic basis of cell identity crisis in cancer has opened the door to the discovery of
hundreds of cancer biomarkers and new oncogenic mechanisms and therapeutic targets.
Abstract
We are developing an original research line on male genome programming, which not only sheds light
on the obscure, yet fundamental and conserved process of male epigenome establishment, but also
generated important new concepts applicable to epigenetics and chromatin biology in general. This research
program also led to unexpected applications in cancer biology. Consequently, a new approach to cancer is
in development in our laboratory, revealing novel oncogenic mechanisms, powerful biomarkers, as well as
pointing to novel therapeutic targets. All this research activity is led on a highly collaborative basis involving
leading international groups in a multidisciplinary approach, including clinicians (France, USA, China),
structural biology, proteomics, genomics and chemical genomics, as illustrated by the publications from our
group reporting collaborative efforts of more than ten independent international laboratories.
Selected references
Grants
• ITN European grant FP7
• INCa
• ANR
Major publications over the past four years
• Reynoird et al. Embo Journal 2010 29: 2943-2952.
• Tan et al. Cell 2011 146: 1015-1027.
• Rousseaux et al. Science Transl Med. 2013 May 22;5(186):186ra66
• Emadali et al. EMBO Mol Med. 2013 Aug;5(8):1180-95
• Montellier et al. Genes Dev. 2013 Aug 1;27(15):1680-92.
• Le Bescont et al. Antioxid Redox Signal. 2014 Mar 6. PMID: 24512221.
• Wang et al. Oncotarget. 2015 May 12. PubMed PMID: 26001296.
Patents
coinventors Pison Rousseaux Sophie, Khochbin Saadi
• In vitro diagnostic method for the diagnosis of somatic and ovarian cancers. UJF oct, 8 2009: wo 2009/121878
• Use of specific genes for the prognosis of lung cancer and the corresponding prognosis method. UJF apr, 26 2012: wo 2012/052524
• Use of specific genes or their encoded proteins for a prognosis method of
classified lung cancer. / UJF apr, 26 2012: wo 2012/052526
Consulting activities
• Occasional consulting for Boehringer Ingelheim (BI), GSK, Sanofi, Ono
Pharmaceuticals, Pierre Fabre; Research collaborations with BI and GSK;
Scientific adviser for CréaCell.
54
Epigenetic and Cell
Signaling
Saadi Khochbin
Business Development Opportunities
Objectives:
• Exploit cancer dependent epigenetically driven gene activation to discover diagnosis/
prognosis biomarkers and new targets for drugs and immunotherapy
• Setup non invasive cancer detection and prognosis tests
• Identify original targets for drugs and immunotherapy
Tools:
• Knowledge driven genome-scale transcriptomic and epigenetic data analyses.
• Tight collaboration with clinicians in lung and breast cancer and in hematological
malignancies.
• Access to tumor banks and direct patient recruitment
Unique selling points:
• Deep knowledge of epigenetic regulations
• Unique translational activity in epigenetics in cancer as well as in other chronic diseases
• Tight interactions between basic scientists, bio-statisticians and bio-computing, and
medical doctors
• An original strategy to identify biomarkers and therapeutic targets applicable to all
cancer types as well as to other chronic diseases
• International network of collaborators, including scientists and clinicians
• Successful marker/target discovery strategy demonstrated in the context lung cancer,
acute leukemia and lymphoma (see publications)
55
Epigenetic and Cell
Signaling
Saadi Khochbin
Project / Expertise
Lung cancer
Pronostic test based on the ectopic activation of male germline genes
Results
• Discovery of 26 male germline genes whose aberrant
expression in lung cancer cells is associated with poor
prognostic
• The same strategy can be used to discover markers in
all cancers
Perspectives
• Routinely predict prognosis of lung tumour patients in
order to adapt the therapeutic strategy.
• Develop screening and follow-up non invasive blood
tests for cancer patients
Acute Lymphoblastic Leukemia (ALL)
Pronostic test based on the ectopic
activation of male germline genes
Results
• Using the same strategy, 6 prognostic marker genes
were discovered and a test was developed to predict the
response to the induction treatment and survival in ALL
children and adult patients
Perspectives
• Routinely predict prognosis of ALL patients in order to
adapt the therapeutic strategy.
• Find new therapeutic targets based on these genes
NUT MIDLINE CARCINOMA
Molecular basis of the oncogenic activity
of BRD4-NUT
Results
• BRD4-NUT induces hyperacetylation feed-forward loop,
leading to the formation of nuclear foci
New epigenetic drugs can disperse the foci and reverse
the oncogenic activity of Brd4-NUT
Perspectives
• Find new targetted therapeutic strategies to treat this
deadly tumour
56
Chromosome instability,
epigenetics and
microRNAs
José Arturo Londoño-Vallejo
MD-PhD
Contact: [email protected]
> Research Center; Town: Institut Curie, Paris 75005
> Administrative affiliations: UMR3244, Institut Curie - CNRS
- UPMC
> Tech Transfer Office: Institut Curie
www.curie.fr
Keywords:
• Telomere
• Chromosome instability (CIN)
• Epigenome
• MicroRNA
Synopsis
We are interested in understanding the mechanisms by which chromosome instability contributes to cancer
Abstract
Our research has shown that chromosome instability due to telomere shortening in human pre-transformed
cells is associated to a genetic reprogramming in which massive microRNA deregulation plays a central
role. The mechanisms responsible for this deregulation are independent of copy number changes and rather
involve a genome-wide redistribution of chromatin marks. On the other hand, the presence of a senescent
microenvironment contributes to the full transformation of CIN+ cells by promoting the acquisition of stemlike traits through another microRNA-depended process also associated to epigenome modifications.
Selected references
Grants
• PAIR prostate 2011-2014
• ITMO epigenetic
Major publications over the past four years
• Terry, S., El-Sayed, I.Y., Destouches, D., Maille, P., Nicolaiew, N., Ploussard,
G., Semprez, F., Pimpie, C., Beltran, H., LONDONO-VALLEJO, A., Allory, Y., de
la Taille, A., Salomon, D.S. and Vacherot, F. (2015) CRIPTO overexpression
promotes mesenchymal differentiation in prostate carcinoma cells through
parallel regulation of AKT and FGFR activities. Oncotarget, 6, 11994-2008.
• Schertzer, M., Jouravleva, K., Perderiset, M., Dingli, F., Loew, D., Le Guen, T.,
Bardoni, B., de Villartay, J.P., Revy, P. and LONDONO-VALLEJO, A. (2015)
Human regulator of telomere elongation helicase 1 (RTEL1) is required for
the nuclear and cytoplasmic trafficking of pre-U2 RNA. Nucleic Acids Res,
43, 1834-47.
• Castro-Vega, L.J., Jouravleva, K., Ortiz-Montero, P., Liu, W.Y., Galeano, J.L.,
Romero, M., Popova, T., Bacchetti, S., Vernot, J.P. and LONDONO-VALLEJO, A. (2015) The senescent microenvironment promotes the emergence of heterogeneous cancer stem-like cells. Carcinogenesis. epub date
2015/07/15.
• Episkopou, H., Draskovic, I., Van Beneden, A., Tilman, G., Mattiussi, M., Gobin, M., Arnoult, N., LONDONO-VALLEJO, A. and Decottignies, A. (2014)
Alternative Lengthening of Telomeres is characterized by reduced compaction of telomeric chromatin. Nucleic Acids Res, 42, 4391-405.
• Castro-Vega, L.J., Jouravleva, K., Liu, W.Y., Martinez, C., Gestraud, P., Hupe,
P., Servant, N., Albaud, B., Gentien, D., Gad, S., Richard, S., Bacchetti, S. and
LONDONO-VALLEJO, A. (2013) Telomere crisis in kidney epithelial cells
promotes the acquisition of a microRNA signature retrieved in aggressive
renal cell carcinomas. Carcinogenesis, 34, 1173-80.
57
Chromosome instability,
epigenetics and
microRNAs
José Arturo Londoño-Vallejo
Business Development Opportunities
Objectives:
• To understand how chromosome instability (CIN) contributes to cancer progression
• To identify key players responsible for epigenome modifications and microRNA
deregulation in response to CIN
• To identify key players responsible for the cancer-promoting effect of the senescent
microenvironment.
Tools:
• NGS: ChIP-seq, RNA-seq, WGS in culture cells and tumor material.
• Genome/Transcriptome analyses in culture cells and tumor material.
• RNA interference, transcriptome and proteomics in culture cells
• Fully annotated prostate cancer specimens and patient cohorts.
58
Chromosome instability,
epigenetics and
microRNAs
José Arturo Londoño-Vallejo
Project / Expertise
Results
• Telomere-driven chromosome instability contribute to the emergence of cancer stem-like cells through epigeneticand microRNA-dependent mechanisms
Perspectives
• Molecular characterization of events responsible for the emergence of cancer stem-like cells
59
Epigenetic and genomic
instability mining in Multiple
Myeloma to define precision
medicine
Jérôme Moreaux
Ph.D.
Contact: [email protected]
> Research Center; Town: Institut de Génétique Humaine (IGH)
Montpellier
> Administrative affiliations: CNRS UPR 1142
> Tech Transfer Office: aXLR
www.axlr.com
Keywords:
• Hematology
• Multiple Myeloma
• Epigenetics
• Genomic Instability/DNA repair
• Haematological malignancies
Synopsis
Treatment improvements will come from detailed molecular analyses to develop individualized therapies
taking into account the molecular heterogeneity and subclonality evolution.
Abstract
Multiple myeloma (MM) is a rarely curable malignant disease of clonal plasma cells that accumulate in the
bone marrow. MM is a genetically and clinically heterogeneous disease. Deep genome sequencing studies
have recently revealed an even wider heterogeneity and genomic instability with the identification of a
complex mutational landscape and a branching pattern of clonal evolution. All patients invariably relapse
after multiple lines of treatment, with shortened intervals in between, and finally become resistant to any
treatment, resulting in loss of clinical control over the disease, and death within weeks.
Treatment improvements will come from detailed molecular analyses to develop individualized therapies
taking into account the molecular heterogeneity, subclonality evolution and drug resistance mechanisms.
Our aim is to understand the mechanisms of drug resistance, define biomarkers and generate assays to
develop precision medicine approach in hematological malignancies (4 patents).
Selected references
Grants
• 2015-2017 : Multiple Myeloma: Epigenetic Mining and Therapeutic Targeting. Cancer Plan-ITMO Cancer. Coordinator: J Moreaux. 500 k€.
• 2015-2018 : Role of RECQ helicases in Multiple Myeloma. INCA PLBIO.
Coordinator: J Moreaux. 575 k€.
• Bret C, Klein B, Moreaux J. Gene expression-based risk score in diffuse
large B-cell lymphoma. Oncotarget. 2012 Dec 31.
• Bou Samra E, Klein B, Commes T, Moreaux J. Development of gene expression-based risk score in cytogenetically normal acute myeloid leukemia
patients. Oncotarget. 2012 Aug 18.
Major publications over the past four years
• In vivo treatment with epigenetic modulating agents induces transcriptional alterations associated with prognosis and immunomodulation in multiple
myeloma. Maes K, De Smedt E, Kassambara A, Hose D, Seckinger A, Van
Valckenborgh E, Menu E, Klein B, Vanderkerken K, Moreaux J*, De Bruyne
E*. Oncotarget. 2014. Dec 26. (* equal contribution)
• Bret C, Klein B, Cartron G, Schved JF, Constantinou A, Pasero P, Moreaux
J. DNA repair in Diffuse Large B-cell Lymphoma: a molecular portrait. Br J
Haematol. 2014. Nov 05.
• Moreaux J, Reme T, Leonard W, Veyrune JL, Requirand G, Goldschmidt H,
Hose D, Klein B. Gene expression based prediction of myeloma cell sensitivity to histone deacetylase inhibitors. British Journal of Cancer. 2013 Aug
6;109(3):676-85.
• Moreaux J, Reme T, Leonard W, Veyrune JL, Requirand G, Goldschmidt H,
Hose D, Klein B. Development of gene expression based score to predict
sensitivity of multiple myeloma cells to DNA methylation inhibitors. Molecular cancer therapeutics. 2012 Oct 18.
Patents
• Method for predicting multiple myeloma treatment response. J Moreaux, B
Klein. PCT/EP2013/069736 and WO2014/044848.
• Method for predicting HDACi treatment response in Multiple Myeloma. J
Moreaux, B Klein. PCT/EP2013/070964.
• Method for predicting DNMTi/HDACi combination treatment response in
Multiple Myeloma. J Moreaux, B Klein. EP14305404.7
• Methods for predicting response to DNA repair pathway inhibitors in diffuse large B-cell lymphoma. J Moreaux, C Bret, G Cartron, A Constantinou,
P Pasero. EP14306201.6
60
Epigenetic and genomic
instability mining in Multiple
Myeloma to define precision
medicine
Jérôme Moreaux
Business Development Opportunities
Objectives:
Multiple myeloma (MM) is a mostly incurable malignant disease of clonal plasma cells
that accumulate in the bone marrow. Our vision is that treatment improvements will come
from detailed molecular analyses to develop individualized therapies taking into account
the molecular heterogeneity and subclonality evolution.
• Characterizing the tumor heterogeneity (genomic and epigenomic diversity) and
understanding how treatment influences intraclonal evolution in MM,
• Understanding the molecular events involved in myelomagenesis and clonal evolution,
• Elucidating the mechanisms of resistance, identifying targets in MM cells to overcome
drug resistance and develop personalized treatments.
Tools:
• Unique collection of Human Myeloma Cell Lines.
• Gene expression profiles of tumor cells from 300 patients at diagnosis, with a careful
patients’ follow-up.
• In vitro model to recapitulate the various steps of human plasma cell. generation.
Unique selling points:
• Expertise in the field of Multiple Myeloma biology.
• Unique collection of Human Myeloma Cell Lines with molecular (RNA seq, Exome seq,
ChIP seq, Methylome, SNP, miRNA, WGS) and drug response characterization.
• Unique in vitro model to recapitulate the various steps of human plasma cell. generation.
• Identification of biomarkers to predict MM cells sensitivity or resistance to treatments (3
patents).
61
Epigenetic and genomic
instability mining in Multiple
Myeloma to define precision
medicine
Jérôme Moreaux
Project / Expertise
Predict response to epigenetic therapy
in MM
Results
• We recently reported gene expression(GEP)based scores to predict the sensitivity of myeloma
cells to different treatments including DNMTi (Moreaux et al. BJH, 2014; Moreaux et al. MCT, 2012)
(Figure 1A&B), HDACi (Moreaux et al. BJC, 2013)
or combination. These scores allow the identification of MM patients who could benefit from HDACi,
DNMTi or DNMTi/HDACi treatment (3 patents).
Perspectives
• Our method could be extended to other drugs
and to other cancers. We are currently expanding
our approach to other treatments used in MM with
the support of the technology transfer acceleration
company SATT AxLR and LR region.
Identification of genes regulated by an epigenetic program and associated with
the pathophysiology of MM : illustration with RECQ1
Results
• We identified RECQ1 among the genes downregulated by DNMT inhibitor. RECQ helicase are
DNA unwinding enzymes involved in the maintenance of chromosome stability. RECQ1 is significantly overexpressed in primary myeloma cells
compared to normal plasma cells. High RECQ1
expression is associated with a poor prognosis
in two independent cohorts of patients. RECQ1
knock down inhibits growth of myeloma cells and
induces apoptosis. RECQ1 depletion induced
spontaneous accumulation of DNA double strand
breaks (DSBs). RECQ1 overexpression significantly protects myeloma cell lines from melphalan
and bortezomib-induced apoptosis. Using immunoprecipitation, RECQ1 was shown to interact
with PARP1. An increased association of the two
proteins was found upon DNA damages induced
by melphalan. In agreement, RECQ1 depletion
sensitizes myeloma cell lines to PARP inhibitor.
Perspectives
• RECQ1 represent a biomarker of drug resistance in MM, which is targeted by DNMT inhibitors. This suggests
association of alkylating agents and/or PARP inhibitors with DNMT inhibitor may represent a therapeutic approach in
RECQ1high patients associated with a poor prognosis.
62
lncRNA and cancer
Antonin Morillon
Ph.D.
Contact: [email protected]
> Research Center; Town: Institut Curie, Paris
> Administrative affiliations: C NRS/PSL-UPMC/Curie
institute
> Tech Transfer Office: Institut Curie
Keywords:
• lncRNA...
• epigenetics...
• chromatin...
• transcription
Synopsis
My group is interested in understanding how Long non coding (lnc)RNA (now representing more than
60 000 genes in humans) control genome expression and maintenance in response to environmental signals
or differentiation programs leading to aggressive cancer forms.
Abstract
We study how lncRNA are expressed and processed and which cellular factors they bind to in response to
environmental signals and differentiation processes. Errors in their expression/localization/functions can
lead to pathological outcomes, such as aggressive cancer. We characterized several lncRNA families from
yeast to human cells in particular those antisense to mRNA. We revealed their wide-spread expression but
also their specificity for different tissues and lineage indicating a key role in cellular identity. We integrated
these findings at the genome-wide level using up to date sequencing technologies and compare their
patterns of expression with epigenetic marks and nuclear configuration. Distinct signatures were defined
among several cancers giving fundamental indications concerning their stage of progression opening new
avenues for diagnostic/prognostic tools.
Selected references
Grants
• ATIP (2006-09)
• ERC starting grant (2009-14)
• ERC consolidator grant (2015-20)
• ANR (2015-18)
Major publications over the past four years
• Li et al. (2015). A Dual Model for Prioritizing Cancer Mutations in the Noncoding Genome Based on Germline and Somatic Events. PLoS Comput
Biol 11(11).
• Descrimes M et al (2015). VING: a software for visualization of deep
sequencing signals. BMC Res Notes. Sep 7;8:419
• Kwapisz et al. (2015) Expression of subtelomeric lncRNAs links telomeres
maintenance to RNA decay in S. cerevisiae. Non-Coding RNA 2015, 1(2),
94-126
• Wery M et al. (2013). Zinc-mediated RNA fragmentation allows robust
transcript reassembly upon whole transcriptome RNA-Seq. Methods. 2013
Sep 1;63(1):25-31.
• Tisseur et al. (2011). Pervasive transcription - Lessons from yeast. Biochimie. 2011 Nov;93(11):1889-96.
• van Dijk et al. (2011). XUTs are a class of Xrn1-sensitive antisense regulatory non-coding RNA in yeast. Nature. 2011 Jun 22;475(7354):114-7.
Patents
• Prostate cancer diagnostic tool (under deposition)
63
lncRNA and cancer
Antonin Morillon
Business Development Opportunities
Objectives:
• to uncover the role of lncRNA in the regulation of cancer progression
• to modulate gene expression and epigenome landscape by controling lncRNA
expression level
• to limit cancer progression through the control of specific key lncRNA
Tools:
• genome wide approaches (RNA-seq, ChIP-seq, NET-seq) and bioinfo analyses
• Access to the curie tumors library
• Human genome editing
• Unique cell culture approaches mimicking cancer EMT
Unique selling points:
• expertise in cryptic lncRNA characterization (genetics and NGS RNA analyses)
• innovative approaches in transcriptomic analyses
• functional characterization of lncRNA candidates
• unique signature profiling of lncRNA for diagnostic and prognostic purposes
• access to tumors library via a variety of cancer tissues
• International visibility and several international collaborations
64
lncRNA and cancer
Antonin Morillon
Project / Expertise
Profiling LncRNA expression in cancer
Results
• A. Schematic view of the process
After RNA extraction and genome-wide comparison, novel lncRNA are characterized. Differential
analyses allowed the identification of a specific
signature that could be used for cancer diagnostic.
• B. Expression clustering of a novel lncRNA signature in prostate cancer by comparing normal
and cancer tissues. Colors represent expression
intensities.
• C. PCA analysis of patients using the novel lncRNA signature. Prostate cancer patient are specifically isolated via the signature.
Perspectives
• Developing rapid and cost effective diagnostic
tools for cancer progression and therapeutic targets.
65
Integrated Functional
Genomic and Biomarkers
Jean MOSSER
PU-PH - Ph.D.
Contact: [email protected]
> Research Center; Town: Institut de Génétique et
Développement de Rennes (IGDR)
Rennes
> Administrative affiliations: CNRS UMR 6290
> Tech Transfer Office: Ouest Valorisation
www.ouest-valorisation.fr
Keywords:
• Epigenetic mechanism
• Somatic or constitutional genetic disease
• Sporadic cancer (e.g. glioblastoma)
• NGS Technology
Synopsis
We look for the molecular elements associated with tumour heterogeneity (in term of aggressiveness and
therapeutic response) in order to improve patients’ molecular stratification.
Abstract
The research interests of the «Integrative Functional Genomics & Biomarkers» team (UMR 6290 IGDR)
revolve around two themes, both focusing on the understanding of the genetic and epigenetic mechanisms
linked to the development of somatic or constitutional genetic diseases. In sporadic cancers (e.g., glioblastoma),
we look for the molecular elements associated with tumour heterogeneity (in term of aggressiveness and
therapeutic response) in order to improve patients’ molecular stratification. In the case of cancer arising
as a complication of a genetic disease like hemochromatosis, we look for the genetic factors modifying
the hemochromatosis-HFE penetrance (GWAS approach, penetrance is considered as a complex genetic
trait). For these two projects, we benefit (i) from regional, national and European cohorts, and (ii) from the
functional genomics approaches made available by the Biogenouest Health Genomic platform (UMS 3480
Biosit ). We use DNA microarrays to identify genes losses and gains and to measure the DNA methylome
that we subsequently correlate with transcriptome data. We complete our study by meta-analyses using
publicly available omic data. We are also developing NGS technology (Next Generation Sequencing) to
identify rare genetic variants of susceptibility for cancers with inappropriate occurring (young age; exome
approach). Ultimately, we use in vitro or in vivo models to validate and decipher the molecular mechanisms
involving some of the genes identified through the genomic discovery process.
Selected references
Grants
• AO Canceropole Grand Ouest 2014
Patents
• US patent application n°14/006023
Major publications over the past four years
• Barlesi et al., Lancet 2015 (in press)
• de Tayrac, Aubry et al., Oncotarget 2015
• Etcheverry, Aubry et al., Plos One 2014
• De Tayrc, Aubry et al., Clinical Cancer Research 2011
• Etcheverry et al., BMC Genomics 2010
• Hervouet et al., Genes Cancer 2010
66
Integrated Functional
Genomic and Biomarkers
Jean MOSSER
Business Development Opportunities
Targeted population
High Grade Glioblastoma (grade IV astrocytoma).
• Prognosis, response to treatment
• Recruitment in clinical trial
• Evaluation tool for new treatment of GBM
Unique selling points
• Improvement in patient molecular stratification (nomogram)
• Higher prediction/pronostication compared to MGMT test
Intellectual property
Prognosis marker
• US patent application n°14/006023
NGS technology
• Dry part - Software filed in APP on 2014
• Wet part - Know-How on FFPE samples preparation
Tools
• Cohort of 399 GBMs homogeneously treated
• Algorithm included 7 parameters (age, KPS, Surgery, IDH1, MGMT, DGKI, TERTp)
• Pyrosequencing technology
67
Integrated Functional
Genomic and Biomarkers
Jean MOSSER
Project / Expertise
epdruGB
Development of an «epidrug» able to sensitize GBM patients to standard treatment (ST)
68
Transcription and
splicing in the context
of chromatin
Christian MUCHARDT
Ph.D.
Contact: [email protected]
> Research Center; Town: Institut Pasteur, Paris
> Administrative affiliations: Institut Pasteur - URA 2578
> Tech Transfer Office: Institut Pasteur
www.pasteur.fr
Keywords:
• Transcription
• Chromatin
• Silencing
• Inflammation
Synopsis
Manage inflammation in breast cancer with small molecules favouring chromatin-dependent gene silencing.
Abstract
In breast cancer, the invasion front forms an inflammatory microenvironment affecting cell identity within
the stroma and favouring epithelial to mesenchymal transition at the edge of the tumour. A range of proinflammatory cytokines involved in this process are regulated by HP1 proteins, a family of chromatindependent transcriptional silencers. The lab is exploring pathways allowing to reinforce the silencing activity
of these proteins with small molecules.
Selected references
Grants
• Carnot initiative GLOBAL CARE
Major publications over the past four years
• Shigella flexneri targets the HP1γ subcode through the phosphothreonine lyase OspF. Harouz H, Rachez C, Meijer BM, Marteyn B, Donnadieu
F, Cammas F, Muchardt C, Sansonetti P, Arbibe L. EMBO J. 2014 Nov
18;33(22):2606-22
• DYRK1A phoshorylates histone H3 to differentially regulate the binding of HP1 isoforms and antagonize HP1-mediated transcriptional repression. Jang SM, Azebi S, Soubigou G, Muchardt C. EMBO Rep. 2014
Jun;15(6):686-94
• Citrullination of histone H3 interferes with HP1-mediated transcriptional
repression. Sharma P, Azebi S, England P, Christensen T, Møller-Larsen A,
Petersen T, Batsché E, Muchardt C. PLoS Genet. 2012 Sep;8(9):e1002934
69
Transcription and
splicing in the context
of chromatin
Christian MUCHARDT
Business Development Opportunities
Objectives:
• Control inflammation in the context of cancer by enhancing the efficiency of chromatindependent transcriptional silencing
Tools:
• Small molecules enhancing transcriptional silencing at pro-inflammatory cytokine
promoters
Unique selling points:
• A novel avenue to the management of inflammation
• A druggable regulator of inducible genes
70
Transcription and
splicing in the context
of chromatin
Christian MUCHARDT
Project / Expertise
A druggable regulator of cytokine genes
Results
• A series of proinflammatory cytokines use HP1
proteins to remain « off » in the absence of pro-inflammatory stimulation.
• This mechanism of repression is highly regulated
by enzymes writing epigenetic marks on histone
H3 (including PADI4).
Perspectives
• Small molecules able to dampen the activity of
these enzymes have the potential to reduce inflammation.
71
Epigenetics
and Cancer
Peter MULLIGAN
Ph.D.
Contact: [email protected]
> Research Center; Town: C
entre de Recherche en
Cancérologie de Lyon (CRCL), Lyon
> Administrative affiliations: Inserm UMR 1052 - CNRS 5286
- Centre Léon Bérard - Université
Claude-Bernard Lyon 1
> Tech Transfer Office: Pulsalys
www.pulsalys.fr
Keywords:
• Epigenetics
• Chromatin Regulation
• Molecular Biology
• Cancer Cell Biology
Synopsis
We purify and characterize chromatin-regulatory complexes containing candidate oncoproteins or tumor
suppressors to understand epigenetic mechanisms in cancer.
Abstract
The NAD+ dependent histone deacetylase SIRT1 promotes chromatin compaction via mechanisms that
include deacetylation of histone H4 lysine 16 (H4K16), acetylation of which is sufficient to prevent higher
order chromatin compaction. SIRT1 also regulates a broad spectrum of cellular and cancer processes,
including genome stability, energy metabolism, apoptosis, cell growth, angiogenesis and metastasis. In order
to understand how this single factor regulates such diverse processes in normal and cancer cells we use
biochemical and molecular/cell biology approaches to identify and validate novel SIRT1-interactors that
might link it to specific gene loci or cellular pathways. The potential of SIRT1 to act as a sensor of abnormal
cancer cell metabolism, an emerging cancer hallmark, is another research interest. Collectively, these studies
will guide preclinical evaluation of SIRT1 as a drug target and development of new epigenetic therapies for
cancer.
Selected references
Grants
• La Fondation pour la Recherche Médicale (FRM) Amorçage de jeunes
équipes 2013, 283000EUR (Awarded November 25th 2013) ; Inserm
CR1 new recruit funding (50K per year, 2015 and 2016).
Major publications over the past four years
• Sedic M, Skibinski A, Brown N, Gallardo M, Mulligan P, Martinez P, Keller
PJ, Glover E, Richardson AL, Cowan J, Toland AE, Ravichandran K, Riethman H, Naber SP, Naar AM, Blasco MA, Hinds PW, Kuperwasser C. (2015).
Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence. Nature Communications, 6, Article number:
7505.
• Toiber D, Erdel F, Silberman DM, Zhong L, Mulligan P, Sebastian C, Cosentino C, Martinez-Pastor B, Giacosa1, Agustina D’Urso S, Naar AM, Rippe K,
and Mostoslavsky R. (2013). SIRT6 recruits SNF2h to sites of DNA breaks,
modulating genomic stability through chromatin remodeling. Molecular Cell.
Aug 22;51(4):454-68; Epub 2013 Jul 31.
• Mulligan P, Yang F, Di Stefano L, Ji JY, Ouyang J, Nishikawa JL, Wang Q,
Kulkarni M, Najafi-Shoushtari SN, Mostoslavsky R, Gygi SP, Gill G, Dyson
NJ and Näär AM. (2011). A SIRT1-LSD1 co-repressor complex regulates Notch target gene expression and development. Molecular Cell. Jun
10;42(5):689-99. Epub 2011 May 19.
• Di Stefano L, Walker JA, Burgio G, Corona D, Mulligan P, Näär AM and
Dyson NJ. (2011). Functional antagonism between histone H3K4 demethylases in vivo. Genes and Development. Jan 1;25(1):17-28.
72
Epigenetics
and Cancer
Peter MULLIGAN
Business Development Opportunities
Objectives:
• Identify epigenetic regulators with potential use as cancer drug targets and/or
biomarkers
• Gain mechanistic insights into gene/genome regulation and cancer hallmark/pathway
regulation by such factors
• Develop therapeutic approaches for cancer based on basic research findings
Tools:
• Biochemical purification and analysis of proteins and complexes
• Molecular/Cell biology assays for functional and mechanistic analysis of candidate
epigenetic regulators of cancer
• Shared institutional core facilities for murine cancer models and high throughput drug
testing/development
Unique selling points:
• Strong track record in both epigenetics and cancer fields from postdoctoral fellowship
(author on first papers describing LSD1 as histone demethylase, and CDYL as
candidate tumor suppressor, for instance)
• Expertise in analysis of histone deacetylase SIRT1
• Team is ideally positioned for cancer research: based in the Cancer Research Center of
Lyon; clinical partnerships with Centre Leon Berard cancer hospital and Hospices Civils
de Lyon.
73
Epigenetics
and Cancer
Peter MULLIGAN
Project / Expertise
Purification and Characterization of Novel
SIRT1–interacting proteins
Results
• Immunopurification of epitope-tagged SIRT1 and mass spectrometry identified polypeptides. Shown is A silver-stained SDS-PAGE gel of the purification. (partially published in Mulligan P. et al., Mol. Cell. 2011)
Perspectives
• Identification of novel SIRT1-interacting proteins was used to show for the first time
that SIRT1 regulates the Notch cellular and cancer signaling Pathway, and interacts
with histone demethylase LSD1 (Mulligan P. et al., 2011). Ongoing work is aimed at
Characterizing other, unpublished, complexes identified.
SIRT1 expression is deregulated in several cancer contexts including familial
BRCA1 mutant breast cancer
Results
• SIRT1 expression is lower in mammary tissues
of women carrying somatic BRCA1 mutations.
(a) Images of IHC staining and quantification of
SIRT1 levels in epithelial cells from WT (n=10)
and BRCA1mut/+ (n=10) breast tissues. Allred
score methodology was used to measure SIRT1
antibody staining. Student’s two-tailed t-test was
used to calculate P value. (*) indicates P value
within the 0.05 level of significance. (Published in
Sedic M, Skibinski A, Brown N, Gallardo M, Mulligan P, et al., Nature Comm., 2015)
Perspectives
• Deregulation of SIRT1 expression in specific
cancer contexts suggests it might be a clinically
useful biomarker in cancer. Current work in our laboratory is aimed at establishing if SIRT1 downregulation in BRCA1 mutant allele carriers might be
a mechanistic event in tumor initiation or malignant progression. These studies will establish if SIRT1 downregulation
is a mechanistic biomarker for breast cancer risk.
74
Molecular Assemblies
and genome Integrity
Françoise OCHSENBEIN
Ph.D.
Contact: [email protected]
> Research Center; Town: Institut de Biologie Intégrative de la
Cellule (I2BC), Gif-sur-Yvette
> Administrative affiliations: C
EA, CNRS UMR 9198
Université Paris-Sud
> Tech Transfer Office: C EA
www.cea.fr
Keywords:
• Histone chaperone
• Replication
• DNA damage signaling
• Evolution
• Epigenetic
Synopsis
Focused on the complexes involved in maintaining genome integrity, we characterize the structure of the
complexes, develop new methods for the prediction of their conformations and design inhibitory compounds
capable of disrupting these interactions.
Abstract
In all leaving systems, genotoxic stresses activate specific interactions networks to protect the genome
and the epigenome. Our team is particularly interested in analyzing the conservation/plasticity of these
networks and to explore how far this information can be used to predict protein-protein interactions mode
or to design molecules that specifically block one of these interactions. We tackle these issues combining
both, experimental and computational approaches. We focus our experimental research on a special class
of protein-protein interaction regulators called assembly chaperones. We are interested in unraveling how
these assembly chaperones promote correct interactions between partners, in the proper cell context, and
at the right moment. We concentrate on histones chaperones that play a central role in regulating DNA
accessibility to replication, transcription, epigenetic modification and repair machineries, and more recently
on proteasome chaperones.
Selected references
Grants
• ANR Chapinhib
• La ligue contre le cancer
• Le Canceropole
Major publications over the past four years
• Jiao, Y., et al. (2012). Surprising complexity of the Asf1 histone chaperoneRad53 kinase interaction. Proc Natl Acad Sci U S A, Feb 21;109(8):286671.
• Abascal F, et al. (2013) Subfunctionalization via adaptive evolution influenced by genomic context: the case of histone chaperones ASF1a and
ASF1b, Mol Biol Evol. Aug;30(8):1853-66
• Pietrobon V, et al. (2014) The Chromatin Assembly Factor 1 Promotes
Rad51-Dependent Template Switches at Replication Forks by Counteracting D-Loop Disassembly by the RecQ-Type Helicase Rqh1, PLoS Biol.
2014 Oct 14;12(10):e1001968
• Andreani J, et al. (2014) Evolution of protein interactions: from interactomes to interfaces. Arch Biochem Biophys. 554:65-75.
• Richet N, et al. (2015) Structural insight into how the human helicase
subunit MCM2 may act as a histone chaperone together with ASF1 at the
replication fork, Nucleic Acids Research 18;43(3):1905-17
Patents
• 1 patent (WO 2013/072636 Al)
75
Molecular Assemblies
and genome Integrity
Françoise OCHSENBEIN
Business Development Opportunities
Objectives:
• Our objectives is to characterize the structure of the complexes, develop new methods
for the prediction of their conformations and design inhibitory compounds capable of
disrupting these interactions. We focused our researches on complexes involved in
maintaining genome and epigenome integrity.
Tools:
• Protein expression and purification for structural biology
• Nuclear Magnetic resonance
• X ray crystallography
• Microcalorimetry
• Protein-protein interaction
• Sequence analysis, coevolution analysis
• Protein evolution
• in silico docking
• Protein/peptide/peptidomimetics in silico design
• Cellular biology
Unique selling points:
• Our team has 20 years expertize in structural biology, protein design and sequencestructure relation prediction
• Since the past decade, we have focused our researches in unravelling the role of
molecular chaperones dedicated to complex assemblies, and more particularly to histone
chaperones.
• In molecular docking we developed new in silico tools incorporating protein coevolution
for the prediction of protein-protein and protein-peptide interaction mode.
76
Molecular Assemblies
and genome Integrity
Françoise OCHSENBEIN
Project / Expertise
CHAPTAR
Results
• Design of specific inhibitor of a histone chaperone and its applications in breast cancer
therapy
Perspectives
• Extend the approach for other applications to
new challenging new target in the epigenetic
area
77
Genetic and Epigenetic
aspects of primary bone
tumors development and bone
mineralization
Benjamin ORY
Ph.D.
Contact: [email protected]
> Research Center; Town: Nantes University Medical School,
Nantes
> Administrative affiliations: INSERM U957, Nantes University
Medical School
> Tech Transfer Office: SATT Ouest Valorisation
www.ouest-valorisation.fr
Keywords:
• microRNAs
• Bromodomain
• HSP
• Primary bone tumors
• Bone mineralization
Synopsis
Our team‘s goal is to uncover the genetic and epigenetic mechanisms underlying the primary bone tumour
development and its associated microenvironment process, the bone mineralisation regulation.
Abstract
Our team focus in particular on cellular stress endured by bone tumour cells as well as the cells belonging
to their direct microenvironment. To reach these goals, we set up a multidisciplinary team composed by
researchers, clinicians, engineers and technicians specialized in the specific aspects of this project. we
propose innovative approaches looking at those physiological and pathological aspects through the prism
of genetic and epigenetic. With a focus on cellular stress, our team plans to understand both critical primary
bone tumour development steps and pathological calcified tissue remodeling.
We make the bet that using different biological contexts and models as diverse as vascular calcifications,
genetic associated bone disorders and primary bone tumours will lead to identify new fundamental pathways
governing bone-remodeling process both in physiological and pathological context.
Selected references
Grants
• Susan Komen
• Regional grant for Epigenetic network
Major publications over the past four years
• Lamoureux F, Baud’huin M, Rodriguez Calleja L, Jacques C, Berreur M,
Rédini F, Lecanda F, Bradner JE, Heymann D, Ory B. Selective inhibition of
BET bromodomain epigenetic signalling interferes with the bone-associated tumour vicious cycle. Nat Commun. 2014 Mar 19.
• Lamoureux F, Baud’huin M, Ory B, Guiho R, Zoubeidi A, Gleave M, Heymann D, Rédini F. Clusterin inhibition using OGX-011 synergistically enhances zoledronic acid activity in osteosarcoma.. Oncotarget. 2014 Aug 4.
• Ramsey MR, Wilson C, Ory B, Rothenberg M, Faquin W, Mills AA and Ellisen LW. FGFR2 signaling underlies p63 oncogenic function in squamous
cell carcinoma. J Clin Invest. 2013 July 8.
• Ory B, Ramsey MR, Wilson C, Vadysirisack DD, Rothenberg MS, Rocco
JW, Ellisen LW.
• A microRNA-dependent program controls p53-independent survival and
chemosensitivity in human and murine squamous cell carcinoma. J Clin
Invest (IF:16.59). 2011; 121(2):809–820.
• Ory B and Ellisen LW. A microRNA-dependent circuit controls p63/p73
homeostasis, cell survival and chemosensitivity: p53 family cross-talk meets
therapeutic opportunity. Oncotarget. 2011; 2(3):259-64.
78
Genetic and Epigenetic
aspects of primary bone
tumors development and bone
mineralization
Benjamin ORY
Business Development Opportunities
Objectives:
• How does the genome integrate intrinsic and environmental signals?
• Epigenetic regulation of gene expression in primary bone tumors and bone
mineralization process
• Identify new genes implicated in bone mineralization regulation
Tools:
• molecular biology
• in vivo models of primary bone tumors, osteoporosis, normal bone physiology
• human samples
Unique selling points:
• expertise in genetic and epigenetic associated to in vivo model
• access to clinical samples of primary bone tumors, ectopic calcification and genetic
associated bone disorders
79
Genetic and Epigenetic
aspects of primary bone
tumors development and bone
mineralization
Benjamin ORY
Project / Expertise
Role of the BET bromodomain proteins in primary bone tumors
BET inhibition represses Osteosarcoma development
Perspectives
80
Genetic and Epigenetic
aspects of primary bone
tumors development and bone
mineralization
Benjamin ORY
Project / Expertise
Role of the microRNAs in Primary Bone Tumor Metastatic Dissemination
ΔNp63α promotes TGFβ-induced metastasis by silencing a microRNA network restraining wound healing
Perspectives
81
B cell diseases and
epigenetics
Yves RENAUDINEAU
PU-PH, PharmD, PhD.
Contact: [email protected]
> Research Center; Town: L
aboratory of Immunology and
Immunotherapy, CHRU Brest
> Administrative affiliations: Inserm ESPRI, ERI29/EA2216
> Tech Transfer Office: SATT Ouest Valorisation,
www.ouest-valorisation.fr
Keywords:
• B cell diseases (cancer, autoimmunity, transplantation)
• DNA methylation/hydroxymethylation
• Human endogenous retroviruses
Synopsis
Understanding the role of DNA methylation/hydroxymethylation in B cells diseases
Abstract
Starting from the observation that DNA demethylation affects human endogenous retrovirus (HERV)
expression in B cells from patients with leukaemia (CLL) and autoimmune diseases (lupus, Sjögren’s
syndrome) we further demonstrated (1) the major consequences of HERV over-expression in B cells, (2) the
pathways regulating DNA methylation in B cells, (3) the reversibility of the process, and (4) the epigenetic
cross-talk between B cells and epithelial cells.
Our research projects combine fundamental tasks (mechanisms controlling DNA methylation/
hydroxymethylation in B cells and its reversibility), clinical tasks (based on the development of NGS using
(hydroxyl)MethylChIPSeq to characterize new biomarkers), and therapeutical tasks (drug candidate discovery).
Selected references
Grants
• Cancéropôle Grand Ouest, Reseau épigénétique
• Association Laurette Fugain
• Ligue contre le cancer
Patents
• Processes for the diagnosis, prognosis and monitoring of the progression
of Chronic Lymphoid Leukaemia (CLL) and/or of Systemic Lupus Erythematosus (SLE) using membrane STIM 1, EP15156694,0
Major publications over the past four years
• Konsta OD in JAI (2016), Font Immunol (2015), Front Genet (2014), eLS
(2015)
• Le Dantec C in Viruses (2015)
• Thabet Y in JAI (2013, 2012)
• Garaud S in J Immunol (2012, 2010, 2009)
• Mankai A in Cancer Res (2008)
82
B cell diseases and
epigenetics
Yves RENAUDINEAU
Business Development Opportunities
Objectives:
• Study the impact of DNA methylation/hydroxymethylation in B cell diseases
• Propose new biomarkers and therapeutic approaches
• Improve existing immunotherapy protocols
Tools:
• Epigenetic plateform (NGS, ChIP…)
• Flow cytometry plateform
• Epigenetic bioinformatic tools (CpG array, MethylChIPSeq…)
• RTqPCR, Western blot, transfection
• Biobank collection with clinical annotation (CLL, autoimmunity…)
Unique selling points:
• Biobank (CLL, autoimmunity…)
• Expertise in B cell diseases
• Expertise in immunotherapy
• Expertise in human endogenous retroviruses
• Large panel of tools including bioinformatic tools to study DNA methylation/
hydroxymethylation
83
B cell diseases and
epigenetics
Yves RENAUDINEAU
Project / Expertise
DNA demethylation/hydroxymethylation in B cells from chronic lymphocytic leukemia
Results
• DNA demethylation/hydroxymethylation characterize CLL B cells
• Modifications associated with disease activity
• Modifications associated with therapeutic response
• Reversible process
Perspectives
• Characterize new biomarkers for
disease activity and therapeutic response
• Develop new epigenetic drugs used
alone or in combination with existing
drugs
Figure 1: B cell lymphoproliferation
characterize chronic lymphocytic
leukemia (A) as well as global DNA
demethylation (5mC) as determined by FACS (B) and after bisulfite
sequencing at gene locus (C).
Infiltrating B cells and tumoral B cells control epithelial DNA demethylation/
hydroxymethylation in MALT lymphoma and Sjögren’s syndrome
Results
• Minor salivary gland DNA demethylation is associated with B
cell infiltration
• Reversible process under antiB cell therapy
Perspectives
• Characterize new biomarkers
for disease activity and therapeutic response
• Develop new epigenetic drugs
used alone or in combination
with existing drugs
Figure 2: The majority of salivary gland MALT lymphoma are though to develop from longstanding Sjögren’s syndrome (SS) and such evolution is associated with important modifications of
DNA methylation in epithelial cells affecting salivary gland functions. Interstingly, such mechanism is reversible (after treatment with rituximab) and related to lymphocyte infiltration.
84
Non-coding RNAs in
development and disease
Claire Rougeulle
PhD.
Contact: [email protected]
> Research Center; Town: E
pigénétique et Destin Cellulaire
(EDC), Paris
> Administrative affiliations: U
niversity Paris Diderot- CNRS;
UMR7216
> Tech Transfer Office: Idfinnov
www.idfinnov.com
Keywords:
• Non-coding RNAs
• Epigenetics
• X-chromosome inactivation
• Stem cells
Synopsis
We investigate the function of non-coding RNAs in controlling gene expression programs in stem cells,
differentiation and development and their involvement in pathological contexts (cancer).
Abstract
Long non-coding RNAs (lncRNAs) play central roles in the epigenetic control of gene expression and they
contribute to cellular identity and cell fate. LncRNAs are also frequently found associated with diseases,
in particular cancers. Our main question is to understand how lncRNAs regulate gene expression and
contribute to cellular identities, in physiological and pathological contexts. Our projects are also devoted to
multi-species analyses to investigate the contribution of lncRNAs to the plasticity of epigenetic regulation
in evolution. We study in particular X-chromosome inactivation (XCI) as one of the most striking example of
developmentally regulated epigenetic processes involving lncRNAs. XCI is tightly linked to cellular state and
instability of XCI is observed in various poorly differentiated contexts including human pluripotent stem cells
and in cancers.
Selected references
Grants
• Programme Avenir 2008-2011
• ERC Starting Grant 2009-2014
• Epigenesys Network of Excellence in Epigenetics and Systems Biology
(FP7-RISE1) 2012-2015
• ANR Générique 2014-2018
Major publications over the past four years
• Vallot* C., Ouimette* JF., Makhlouf M., Féraud O., Pontis J. Côme J., Martinat
C., Bennaceur-Griscelli A., Lalande M. and Rougeulle C. (2015) Erosion of
X chromosome inactivation in human pluripotent cells initiates with XACT
coating and depends on a specific heterochromatin landscape. Cell Stem
Cell. 16: 533-46.
• Chen H., Aksoy I., Gonnot F., Osteil P., Aubry M., Hamela C., Rognard C., Hochard A., Voisin S., Fontaine E., Mure M., Afanassieff M., Cleroux E., Guibert
S., Chen J., Vallot C., Acloque H., Genthon C., Donnadieu C., De Vos J., Sanlaville D., Guérin JF., Weber M., Stanton LW., Rougeulle C., Pain B., Bourillot PY.,
and Savatier P. (2015) Reinforcement of STAT3 activity reprograms human
embryonic stem cells to naïve-like pluripotency. Nature Com. 6: 7095.
• Makhlouf* M., Ouimette* JF., Oldfield* A., Navarro P., Neuillet D. and Rougeulle C. (2014) A prominent and conserved role for YY1 in Xist transcriptional activation. Nature Com. 5, 4878.
• Vallot C., Huret C., Lesecque Y., Resch A., Oudrhiri N., Bennaceur-Griscelli
A., Duret L. and Rougeulle C. (2013) XACT, a long non-coding transcript
coating the active X chromosome in human pluripotent cells. Nature Genet.
45:239-41. Epub Jan 20.
• Chureau C., Chantalat S., Romito A., Galvani A., Duret L., Avner P. and
Rougeulle C. (2011) Ftx is a non-coding RNA which affects Xist expression
and chromatin structure within the X-inactivation center region. Hum. Mol.
Genet., 20: 705-718.
Patents
• Rogner U., Spyropoulos D., Rougeulle C. and Avner, P. (2000) Identification
of neural defects associated with the Nucleosomal Assembly Protein 1l2
Gene. US Patent n°202 111.
85
Non-coding RNAs in
development and disease
Claire Rougeulle
Business Development Opportunities
Objectives:
• To characterize the molecular network controlling X-chromosome inactivation in mouse
and human and to determine the contribution of long non-coding RNAs (lncRNAs) to
species-specific variations
• To address the link between lncRNA, pluripotency, differentiation and development
• To investigate on a larger scale the contribution of lncRNAs and epigenetic alteration to
pathological states (cancer)
Tools:
• Mouse and human pluripotent stem cells coupled to animal models
• State of the art genome engineering
• Transcriptomic and epigenomic approaches (RNA-seq and ChIP-seq)
• Single cell imaging
Unique selling points:
• Multispecies analysis of long non-coding RNAs and epigenetic regulations
• Development of a unique approach to visualize chromosome transcription territories
• Combined expertise in mouse and human pluripotent stem cells
• Genome engineering in human pluripotent stem cells
• Animal models for long non-coding RNAs
• Investigation of epigenomic and transcriptomic alterations in pathologies (autism,
cancer) through collaborations
86
Non-coding RNAs in
development and disease
Claire Rougeulle
Project / Expertise
Contribution of the long non-coding RNA Ftx to X-inactivation and cell differentiation
Results
• Identification of Ftx, a conserved X-linked lncRNA,
which produces several nuclear isoforms and contains
intronic miRNAs deregulated in cancer
• Ftx expression peaks at the onset of X-inactivation (A)
• Impaired X-inactivation in Ftx mutant cells, as monitored by counting the number of cells with Xist RNA
cloud (B)
• Impaired differentiation of Ftx mutant cells (C)
Perspectives
• We are exploring the function of Ftx ex vivo (ES cells)
and in vivo (KO mice)
• We are studying the function of the FTX human ortholog
• We are investigation the putative contribution of Ftx
and of the embedded miRNAs to cancer
Regulation of X chromosome inactivation in humans
Results
• Characterization of a pluripotent-specific epigenomic landscape of the inactive X chromosome (ChIPseq, A)
• Identification of XACT, a human-specific long noncoding RNA (RNA-seq, B)
• XACT coats the active X chromosome in human
pluripotent stem cells (PSC) (RNA-FISH, C)
• XACT expression is restricted to pluripotent cells
and correlates with unstable X-inactivation (RNAFISH, D)
Perspectives
• We are addressing the function of XACT and the
mechanisms by which it coats active X chromosomes
• We are aslo exploring the contribution of XACT to
unstable X-inactivation in cancer
87
Laboratory for Epigenetics
& Environment
Jörg Tost
PhD, Head Laboratory for Epigenetics
& Environment
Contact: [email protected] - [email protected]
> Research Center; Town: C
EA - Institut de Génomique, Centre
National de Génotypage, Evry
> Administrative affiliations: C
EA
> Tech Transfer Office: D SV/CEA, Partenariats industriels et
valorisation
Keywords:
• EPIGENOMICS
• DNA METHYLATION
• BIOINFORMATICS
• DATA INTEGRATION
Synopsis
The Laboratory for Epigenetics & Environment has set-up a high-throughput environment for the accurate
and comprehensive analysis of the multilayered epigenome using state-of-the-art technologies and the
associated bioinformatic and data integration tools, that is unique in France.
Abstract
The laboratory works on the development and application of technologies to analyze DNA methylation and
other epigenetic modifications including histone modifications, chromatin accessibility as well as small and
long non-coding RNAs. Technologies have been implemented for both investigating target loci at highresolution and comprehensive genome-wide analyses. The second research area is the development of
bioinformatic and biostatistic tools for the processing of such data. The main focus of the Epigenetics
group has been the analysis of DNA methylation patterns implicated in tumorigenesis more recently the
alteration of the epigenetic profiles in function of environmental exposure. The laboratory has authored or
co-authored more than 100 publications in the last ten years. In the field of cancer epigenetics the research
programs address particularly the integrated analysis of epigenetic modifications in breast and renal cancer
(EU funded ICGC project), melanoma and neuroendocrine tumors.
Selected references
Grants
• INCa: Translational Cancer Research Mechanisms of tissue invasion in
neuroendocrine tumors: towards a concept of epithelio-neural transition ?
(2015-2018).
• Aviesan/INSERM: Molecular dissection of epigenetic mechanisms of
MEN1/MLL and MEN1//PcG/YY1 complexes involved in the tumorigenesis of islet cells (DEMENIS)(2014-2017).
• Aviesan/INSERM: EpiChem-Seq: Chemical scanning of DNA methylation
in leukemia progression and maintenance, (2014-2017).
• EU FP7 READNA: Revolutionary Approaches for DNA analysis (20092012).
• EU FP7 CAGEKID: Cancer genomics of the kidney (2010-2014).
Major publications over the past four years
• Myrtue Nielsen, H., How-Kit, A., Guerin, C., Castinetti, F., Moen Vollan, H.
K., De Micco, C., Daunay, A., Taieb, D., Van Loo, P., Besse, C., Kristensen, V.N.
Hansen, L.L., Barlier, A., Sebag, F., and J. Tost (2015) Copy number variations alter methylation and parallel IGF2 overexpression in adrenal tumors,
Endocrine Rel. Cancer, 22, 953-967.
• How Kit, A., Dejeux, E., Dousset, B., Renault, V., Baudry, M., Terris, B. and
J. Tost (2015) DNA methylation profiles distinguish different subtypes of
gastroenteropancreatic neuroendocrine tumors. Epigenomics, in press.
• Klajic, J., Busato, F., Edvardsen, H., Touleimat, N., Fleischer, T., Bukholm, I.
R., Borresen-Dale A.-L., Lonning, P. E., Tost, J., V. N. Kristensen (2014) DNA
Methylation status of key cell cycle regulators such as CDKNA2/p16 and
CCNA1 correlates with treatment response to doxorubicin and 5-fluorouracil in locally advanced breast tumors. Clin Cancer Res., 20, 6357-6366.
• Scelo, G., Riazalhosseini, Y., Greger, L., Letourneau, L., …Tost, J., Banks, R.E.,
Brazma, A.and G. M. Lathrop GM. (2014) Variation in genomic landscape of
clear cell renal cell carcinoma across Europe. Nat. Commun., 5, 5135.
• Fleischer, T., Frigessi, A., Johnson, K.C., Edvardsen, H., Touleimat, N., Klajic,
J., Riis, M., Haakensen, V.D., Wärnberg, F., Naume, B., Helland, A., Børresen-Dale, A.-L., Tost, J., Christensen, B.C. and V.N. Kristensen (2014) Genome-wide DNA methylation profiles in progression to in situ and invasive
carcinoma of the breast with impact on gene transcription and prognosis.
Genome Biology, 15, 435.
• Fleischer, T., Edvardsen, H., Solvang, H.K., Daviaud, C., Naume, B., Børresen-Dale, A.-L., Kristensen, V., and J. Tost (2014) Integrated analysis of
high-resolution DNA methylation profiles, gene expression, germline genotypes and clinical end points in breast cancer patients. Int. J. Cancer, 134,
2615-2625.
• Touleimat, N., and J. Tost (2012) A complete pipeline for Infinium Methylation 450K BeadChip data processing using subset quantile normalization
for accurate DNA methylation estimation, Epigenomics, 4, 325-341.
88
Laboratory for Epigenetics
& Environment
Jörg Tost
Business Development Opportunities
Objectives:
• Analyze comprehensively the different layers of the epigenome using state-of-the-art
high-throughput technologies
• Develop and implement the bioinformatic and biostatistical tools to analyze the
generated data
• Develop molecular signatures for the prediction and monitoring of the response to
treatment, assessment of the metastatic potential and other parameters of clinical
interest
Tools:
• High-throughput technologies for DNA methylation analysis (NGS, BeadArrays,
Pyrosequencing)
• Chromatin analysis (ChIP-seq/ATAC-seq)
• Small RNA and long (non-coding) RNA analysis (RNA-seq, smallRNA-seq)
• Bioinfomatics/Biostatistics/Data integration
Unique selling points:
• Large variety of of state-of-the art technologies and protocols (NGS, microarray)
implemented to comprehensively analyze the different layers of the epigenome
• Standardized data processing with comprehensive quality control tools and visual
exploratory analyses
• Quantitative high-resolution technologies for validation and replication available
Technological and bioinformatic expertise
• Biostatistical algorithms for e.g. determining epigenetic small signatures for the
prediction of response based on epigenetic markers
• Data integration of the analyzed epigenetic, genetic and transcriptomic alterations with
public databases
89
Laboratory for Epigenetics
& Environment
Jörg Tost
Project / Expertise
Functional annotation of non-coding mutations using high-throughput epigenomic
data in ccRCC
Results
• Functionally relevant mutations were identified in active regulatory elements of ccRCC. The use of whole-genome sequencing data of 100 patients affected by ccRCC and epigenetic
data (ChIP-seq and ATAC-seq) from renal cancer cell lines and
normal renal tissue lines enabled the identification of mutation
islands located in those regulatory elements. Among those, numerous mutated promoters have previously been shown to be
involved in urogenital cancers. Moreover, the use of RNA-seq
data highlighted the association between some mutation islands
and gene expression changes.. This pioneer work in the integration of genetic and epigenetic data consists describes for
the first time non-coding mutations located on active regulatory
elements identified on a cell type relevant to the study.
Perspectives
• The decrease of sequencing costs will enable to obtain whole genome coverage of cancer-related mutations in
larger cohorts of ccRCC patients facilitating the identification of recurrent mutations in gene regulatory elements
identified in disease relevant cell types.
DNA methylation based signatures to predict treatment outcome for personalized
cancer therapy
Results
• There is currently great interest in mutation detection for the
genotype-driven personalized treatment of cancer patients.
However, the response of each patient is variable and molecular signatures to predict the response prior to start of the treatment would allow to select the most efficient and best-tolerated
treatment of each patient. We used the DNA methylation profile
of 450K CpGs throughout the genome to develop a predictive
signature for the response to vemurafenib in BRAF mutated
metastatic melanoma patients. A suite of prediction algorithms
based on mutational information criteria and normalized graph
cut algorithms was used to reduce the dimensions of the data
set while maximizing the recognition ratio of desired signals and
at the same time minimize the classification error for recognition
tasks. A signature of 9 CpGs was predictive for the non-response to the investigated treatment
Perspectives
• The developed methylation signature is currently under investigation in a replication cohort. With the adaption of the
treatment scheme in the clinics the signatures will be continuously revised in function of the commonly used treatment
regimens.
90
Control of Gene
Expression
Michele TRABUCCHI
Ph.D.
Contact: [email protected]
> Research Center; Town: C
entre Méditerranéen de Médecine
Moléculaire (C3M), Nice
> Administrative affiliations: Inserm U1065, Université NiceSophia-Antipolis
> Tech Transfer Office: Inserm Transfert
www.inserm-transfert.fr
Keywords:
• Gene expression control
• Noncoding RNAs
• Ribonucleoprotein complex
• Protein/RNA interaction
Synopsis
Integrated point of view of gene expression from molecular, biochemical, bioinformatics approaches and
validation in vivo or in patient cohorts.
Abstract
Small RNAs are crucial components of gene expression regulation and play a role in many biological
processes including development and tissue homeostasis, and pathogenesis. Over the past years, we
have used high-throughput transcriptomic and proteomic analyses, coupled with in vivo studies in animal
models and patient cohorts, documenting the importance of the generation of novel classes of small RNAs
that operate through a very complex network of interactions to finely control gene expression programs in
physiopathological events. A proteomic approach has been used to identify complexes involved in biogenesis
and targeting mechanisms of regulatory small RNAs, and a deep sequencing one to determine the regulation
of direct target RNAs. In collaboration with clinical-oriented teams, we are investigating the implication of the
discovered mechanisms in pathological events.
Selected references
Grants
• ITMO Cancer
• FRM Equipe
Major publications over the past four years
• P. Briata, W.J. Lin, M. Giovarelli, M. Pasero, C.F. Chou, M. Trabucchi, M.G.
Rosenfeld, C.Y. Chen, R. Gherzi (2012). PI3K/AKT signaling determines a
dynamic switch between distinct KSRP functions favoring skeletal myogenesis. Cell Death & Differ Mar;19(3):478-87.
• E. Repetto, P. Briata, N. Kuziner, B.D. Harfe, M.T. McManus, R. Gherzi, M.G.
Rosenfeld, M. Trabucchi (2012) Let-7b/c enhance the stability of a tissuespecific mRNA during mammalian organogenesis as part of a feedback
loop involving KSRP. Plos Genetics Jul;8(7): e1002823.
• Q. Hu, B. Tanasa*, M. Trabucchi*, W. Li, J. Zhang, K.A. Ohgi, D.W. Rose, C.K.
Glass, M.G. Rosenfeld (2012) DICER- and AGO3-dependent generation of
retinoic acid-induced DR2 Alu RNAs regulates human stem cell proliferation. Nature structural & molecular biology 19:1168-1175.
• S. Bottini, A. Bernini, M. De Chiara, D. Garlaschelli, O. Spiga, M. Dioguardi,
E. Vannuccini, A. Tramontano, N. Niccolai (2013) ProCoCoA: a quantitative
approach for analyzing protein core composition. Computational biology and
chemistry 43:29-34.
• S. Saccani and M. Trabucchi (2015) Regulation of stimulus-inducible gene
expression in myeloid cells. Seminars in Immunology. (Review)
• E. Repetto, L. Lichtenstein, Z. Hizir, N. Tekaya, M. Benahmed, J.B. Ruidavets, L.E. Zaragosi, R. Ruimy, J. Ferrières, P. Barbry, L.O. Martinez, M. Trabucchi. (2015) RNY-derived small RNAs as a signature of Coronary Artery
Disease. BMC Medicine (Accepted).
Patents
• n° EP 13 306 439.4 –Dosage of RNY-derived small RNAs as a novel
biomarkers for atherosclerosis related disorder, the coronary artery disease
(2013).
91
Control of Gene
Expression
Michele TRABUCCHI
Business Development Opportunities
Objectives:
• How do noncoding RNAs regulate gene expression (biochemical mechanisms in both
immune and tumoral cell models)?
• What is the function of noncoding RNAs in the pathogenesis of inflammatory diseases
sensu lato?
• How would environmental cues dysregulate expression and function of noncoding
RNAs?
Tools:
• mass-spectrometry analyses to investigate the function and the dynamism of
ribonucleoprotein complexes associated to noncoding RNAs
• high-throughput sequencing approaches to study expression regulation of noncoding
RNAs and target-RNAs of RNA binding proteins (such as Gro-seq and CLIP-seq)
• Transgenic animal models to investigate the function of noncoding RNAs in the
pathogenesis of human disorders.
Unique selling points:
• Strong background and expertise in RNA biology and gene expression control fields,
recognized by successfully developing a series of important, complex stories to the point
that they survived scrutiny at the most rigorous journals, including Nature, Nature Struct &
Mol Biol, Plos Genetics, and BMC Medicine
• From molecular to clinical study: integrated point of view of gene expression from
molecular, biochemical, bioinformatics, in cells, ex vivo, in vivo, to patient cohorts
92
Control of Gene
Expression
Michele TRABUCCHI
Project / Expertise
Subject 1
Results
• Our data published in Nature (2009)
elevated the terminal loop of miRNA
precursors as important element to
harbor RNA-binding proteins to finely
modulate miRNA processing in a cell
type specific fashion,
Perspectives
• Basic research on novel Mechanisms of gene Expression control
mediated by miRNAs
Subject 2
Results
• KSRP-dependent expre-ssion
of miR-155 regulate the inflammatory respo-nse in activated
macro-phages
Perspectives
• Studying the pathological role
of miR-155 and its mode of action in a mouse model forbreast
cancer (MMTV-PyVT mouse line)
93
Epigenetics and epithelial
stemness, differentiation
and carcinogenesis
Isabelle VAN SEUNINGEN
Ph.D.
Contact: [email protected]
> Research Center; Town: J ean-Pierre Aubert Research Center,
Lille, France
> Administrative affiliations: Inserm UMR-S 1172, Université
de Lille, CHRU de Lille
> Tech Transfer Office: SATT Nord
sattnord.fr
Keywords:
• Mucin
• Cancer
• Epigenetics
• Epithelium
• Gastrointestinal
Synopsis
Our laboratory studies mechanisms of tumor resistance to chemotherapeutic drug treatments and the role
of epigenetics in stem cell plasticity. A focus is made on the role of oncogenic mucins in these processes.
Abstract
1- Role of MUC1 and MUC4 mucins in pancreatic, oeso-gastric, colonic and renal carcinogenesis and
tumor resistance. In vitro (2D and 3D cell lines), in vivo (animal models) and ex vivo (patient material) studies.
Regulation, intracellular signalling, structure-function relationship, intracellular trafficking.
2- Epigenetic regulation (DNA methylation, histone modifications) and regulation by miRNA of the 11p15
mucin genes and of MUC1 and MUC4 mucin genes in epithelial cancers. Application to the prognosis/
classification of epithelial tumors,
3- Cancer stem cell, chemoresistance, and tumor dormancy (model of the intestinal crypt-villus axis),
4- Translational research with hospital partners. Mucins and other markers as diagnostic/prognostic,
predictive factors (therapy orientation), patient management.
Selected references
Grants
• Equipe labellisée LIGUE 2007-2013 : MUC4-ErbB2 and pancreatic cancer chemoresistance
• ANR 2016-2018: DRUG_MUC4, SIRIC ONCOLille, LNCC, Région NPdC.
Major publications over the past four years
• Skrypek N, Vasseur R, Vincent A, Duchêne B, Van Seuningen I, Jonckheere
N. The oncogenic receptor ErbB2 modulates gemcitabine and irinotecan/
SN-38 chemoresistance of human pancreatic cancer cells via hCNT1 transporter and multidrug-resistance associated protein MRP-2. Oncotarget.
2015 May 10;6(13):10853-67.
• Vincent A, Kazmierczak C, Duchêne B, Jonckheere N, Leteurtre E, Van
Seuningen I. Cryosectioning the intestinal crypt-villus axis: an ex vivo
method to study the dynamic of epigenetic modifications from stem cells to
differentiated cells. Stem Cell Res. 2015 Jan;14(1):105-13
• Renaud F, Vincent A, Mariette C, Crépin M, Stechly L, Truant S, Copin
MC, Porchet N, Leteurtre E, Van Seuningen I*, Buisine MP*. MUC5AC
hypomethylation is a predictor of microsatellite instability independently of
clinical factors associated with colorectal cancer. Int J Cancer. 2015 Jun
15;136(12):2811-21
• Skrypek N, Duchene B, Hebbar M, Leteurtre E, Van Seuningen I, Jonckheere N. The MUC4 mucin mediates gemcitabine resistance of human
pancreatic cancer cells via the concentrative nucleoside transporter family.
Oncogene, 2013 Mar 28;32(13):1714-1723
• Jonckheere N, Skrypek N, and Van Seuningen I. Mucins and tumor resistance to chemotherapeutic drugs. Biochim Biophys Acta (BBA) - Reviews
on Cancer 2014 Apr 29;1846(1):142-151
• Vincent A, Van Seuningen I. On the epigenetic origin of cancer stem cells.
Biochim Biophys Acta -Rev Cancer. 2012 Apr 1;1826(1):83-88
• Jonckheere N, Skrypek N, Frénois F, Van Seuningen I. Membrane-bound
mucin modular domains: from structure to function. Biochimie, 2013
Jun;95(6):1077-86
94
Epigenetics and epithelial
stemness, differentiation
and carcinogenesis
Isabelle VAN SEUNINGEN
Business Development Opportunities
Objectives:
• Develop specific epidrugs targeting proteins involved in stem cell differentiation
• Develop specific drugs (PPI inhibitors) of the MUC4-ErbB2 oncogenic complex
Tools:
• Collection of human and murine 3D cellular models (colon, pancreas, stomach, kidney)
• Transgenic mouse of pancreatic carcinogenesis (Pdx-1-Cre;LStopL-KrasG12D)
• Muc1, Muc4, Muc2, Muc5ac KO mice models
Unique selling points:
• International visibility and expertise on mucin biology
• Discovery of 3 mucin genes: MUC4, MUC5AC and MUC5B.
• Unique and specific (antibodies, promoter constructs) tools to study genes encoding
mucins and translated products (= high molecular weight O-glycoproteins)
• 3D organoids expertise and collection of 3D cellular models (pancreas, colon, stomach,
kidney)
• CRISPR-Cas9 technology to develop new and unique 3D cellular models
95
Epigenetics and epithelial
stemness, differentiation
and carcinogenesis
Isabelle VAN SEUNINGEN
Project / Expertise
Mucins, ErbBs and tumor chemoresistance
Results
• We have deciphered the mechanisms of
tumor resistance linked to MUC1 and MUC4
mucin altered expression in epithelial cancer
cells. We have also shown that their membrane partners (ErbB receptor family) are
also involved in these resistance mechanisms
(Jonckheere et al., BBA-Rev Cancer 2014).
We have identified the mechanism of interaction between MUC4 and ErbB2 in human cancer cells (Jonckheere et al., Biochimie 2013).
Perspectives
• We want to develop specific drugs (proteinprotein interaction inhibitors) targeting MUC4
domains (ANR 2016-2018) to inhibit oncogenic activity of MUC4-ErbB2 complex. We also
want to target proteins conveying tumor resistance linked with overexpression of MUC4-ErbB2 and MUC1-EGFR complexes.
Epigenetics and cancer stem cell plasticity
Results
• We have started characterizing epigenetic landscapes to discriminate aberrant marks (good candidates for tumour detection) from cancer stem
cell specific profiles (Vincent and Van Seuningen,
BBA-Rev Cancer 2012). We also have set up an
original method of crypt-villus axis cryosectioning
to precisely study epigenetic modifications during
the differentiation process (Vincent et al., Stem Cell
Res 2015). We have also set-up 3D organoids models to develop a 3D biobank to screen efficiency of
future epidrugs that we will design.
Perspectives
• We want to identify what epigenetics can teach us
about the origin of cancer stem cells. We also want
to identify epigenetic reprogramming processes
to design new epidrugs that will specifically target
cancer stem cells.
96
RNA and Epigenetics
André VERDEL
Ph.D.
Contact: [email protected]
> Research Center; Town: Institut Albert Bonniot (IAB), Grenoble
> Administrative affiliations: Inserm U823/Université Grenoble
Alpes
> Tech Transfer Office: Floralis
www.floralis.fr
Keywords:
• ARN
• Epigenetics
• Chromatin
• Transcription
• Transcriptomics
• Proteomics
Attractive synopsis
We used the yeast model system to uncover new epigenetic mechanisms part of which are likely to be
conserved in human and involved in cancer.
Abstract
Recently, the process of RNA interference (RNAi) was found to act on, or near, chromatin in many eukaryotes
including fungi, plants, drosophila and vertebrates. In the fission yeast Schizosaccharomyces pombe,
where the molecular mechanisms are among the most detailed, RNAi silences transcription by triggering
formation of heterochromatin. Heterochromatin is conserved among eukaryotes and plays essential roles in
chromosome segregation and in maintenance of genomic stability. Heterochromatin or heterochromatin-like
structures are involved in long-term silencing of key genes during cellular differentiation and development.
As a consequence, malfunctions in heterochromatin assembly greatly contribute to the appearance or
progression of various diseases, such as cancer.
Our team focuses on understanding how RNA can modulate gene expression in an epigenetic manner by
acting directly on the chromosome.
By coupling innovative and interdisciplinary approaches to classical yeast molecular genetics, protein
affinity purifications and microscopy techniques we are exploring fundamental aspects of RNA-driven
heterochromatin formation in fission yeast. As RNA-based chromatin modification is evolutionary conserved,
our studies have the potential to bring general insights into how RNA modulates chromatin structure and
function in humans.
Selected references
Major publications over the past four years
• Hiriart E, Verdel A. Chromosome Res. 2013 Dec;21(6-7):653-63. doi:
10.1007/s10577-013-9393-5 Long noncoding RNA-based chromatin
control of germ cell differenciation: a yeast perspective
• Yamashita A, Shichino Y, Tanaka H, Hiriart E, Touat-Todeschini L, Vavasseur
A, Ding DQ, Hiraoka Y, Verdel A, Yamamoto M. Open Biol. 2012 Hexanucleotide motifs mediate recruitment of the RNA elimination machinery to
silent meiotic genes. Mar;2(3):120014. doi:10.1098/rsob. 120014.
• Hiriart E, Vavasseur A, Touat-Todeschini L, Yamashita A, Gilquin B, Lambert
E, Perot J, Shichino Y, Nazaret N, Boyaukt C, Lachuer J, Perazza D, Yamamoto M, Verdel A. EMBO J. 2012 May 16;31(10)/2296-308. doi:10.1038/
emboj.2012.105. Epub 2012 Apr 20 Mmi1 RNA surveillance machinery
directs RNAi complex RITS to specific meiotic genes in fission yeast.
97
RNA and Epigenetics
André VERDEL
Business Development Opportunities
Tools:
• We use yeast as a reference model to study epigenetic mechanisms, as well as high
throughput sequencing, transcriptomics and state of the art quantitative preteomics, in
addition to classical yeast genetics, molecular and cellular biology.
98
Molecular basis of glioma
cancer stem cells properties
and functional intra tumor
heterogeneity
Thierry Virolle
Ph.D.
Contact: [email protected]
> Research Center; Town: Institut de Biologie Valrose (iBV)
Nice
> Administrative affiliations: Inserm U 1091 - CNRS UMR
7277 - Université Nice Sophia
Antipolis
> Tech Transfer Office: Inserm Transfert
www.inserm-transfert.fr
Keywords:
• Cancer stem cells
• Glioblastoma
• Chemical compounds
• Differentiation
Synopsis
Innovative therapeutic strategy against cancer stem cells using chemical compounds: turning glioma stem
cells into indolent cells.
Abstract
Glioblastomas (GBM) are the most common form of primary brain tumors afflicting adult patients of all
ages. These vascularized and infiltrating tumors remain incurable and lead to a fatal outcome in less than
18 months. One of the most striking features of GBM functional heterogeneity resides in the coexistence of
GBM stem-like or progenitor cells (GSC) and non mitotic, indolent differentiated cells, in variable proportions.
Such a functional heterogeneity confuses the prognosis and constitutes a major difficulty for conventional
anti-tumor therapies because of the persistence of GSC. By combining molecular/cellular biology and
chemical studies in collaboration with Dr M Duca (ICN, Nice), two complementary disciplines, we have
designed and characterized chemical compounds capable of turning GSC into indolent cells, constituting
putative innovative therapeutic agents.
Selected references
Grants
• CANCEROPOLE PACA (2015)
• ANR
• INCA PLBIO
Major publications over the past four years
• Vo DD …..Duca M. ACS Chem Biol. 2014
• Fareh M …… Virolle T. Cell Death Differ. 2012
• Turchi L …… Virolle T. Stem Cells. 2013
• Burel-Vandenbos F…… Virolle T. Neuro Oncol. 2013
• Nayernia Z ….. Virolle T*, Preynat Seauve O*. (equal contribution). Biomaterials. 2013
Patents
• Brevet publié : FR2963020 - WO2012010768 A1 – Procédé d’obtention
d’un extrait et extrait pour le traitement d’un cancer. 27/01/2012- UNSA
N/REF FR1059250.
• Demande de dépôt de brevet Europeen 21 June 2013: submission number 1000197860, applicant number EP13305855.2.
• Déclaration d’invention et demande de dépôt de brevet 2015 pour le composé DVXXX. Etude de brevetabilité positive, cabinet Becker & associés. V/
REF : 696 GB épigénétique N/REF : DB1773, cabinet BECKER & associés.
99
Molecular basis of glioma
cancer stem cells properties
and functional intra tumor
heterogeneity
Thierry Virolle
Business Development Opportunities
Objectives:
• Targeting glioblastoma stem cells through their commitment into indolent tumor cells
Tools:
• Primary culture of glioblastoma stem cells/ tumor tissues
• Small molecule compounds
• miRNA
Unique selling points :
• Innovative therapeutic approach based on physiological commitment of cancer stem
cells into a more differentiated indolent tumor cell
• Use of small molecule compounds capable of targetting key miRNA involved in cancer
stem cell plasticity
• Combination of these small molecule compounds with the treatement of reference
against glioblastoma
100
Molecular basis of glioma
cancer stem cells properties
and functional intra tumor
heterogeneity
Thierry Virolle
Project / Expertise
Targeting glioblastoma stem cells
Results
• DVXXX and derivative molecules are capable
to inhibit stemness and clonal prolifération of
glioma stem cells.
• DVXXX and derivative molecules sensitize glioma stem cells to Temodal treatment (treatment
of reference for glioblastoma)
• No toxicity
Perspectives
• Proof of principle in vivo
• Clinical trials
101
Molecular and Cellular
Biology of HNSCC and
Prostate Cancer
Bohdan Wasylyk
BSc, Ph.D.
Contact: [email protected]
> Research Center; Town: Institut de Génétique et de Biologie
Moléculaire et Cellulaire (IGBMC)
Strasbourg
> Administrative affiliations: C
NRS UMR 7104 - Inserm U
964 - Université de Strasbourg
> Tech Transfer Office: Conectus
www.conectus.fr
Keywords:
• Biomarkers
• Therapeutic targets
• Multi-omics
Synopsis
We generate foundational discoveries with clinical perspectives using an approach that flows from the
patient to the laboratory and back to the patient, and combines unique state-of-the-art methodology, preclinical models, clinical expertise, patient samples and bioinformatics.
Abstract
HNSCC (Head and Neck Squamous Cell Carcinoma) is a prevalent cancer with poor prognosis and an urgent
need for new therapeutic options and biomarkers. In a collaboration between the IGBMC (a world renowned
research institute), clinicians at the Strasbourg Cancer Hospital (Centre Paul Strauss) and the bioinformatics
team of the National Cancer Ligue (CIT program), we have used high-quality patient material and different
whole genome approaches (DNA methylation, miRNAs, mRNAs, DNA copy number) to identify pathways
associated with poor prognosis and propensity for future metastasis. We are currently validating a unique
miRNA signature for poor prognosis and exploiting the miRNAs for therapeutic purposes. Bioinformatic
analysis of available datasets (including TCGA,The Cancer Genome Atlas) has led to the identification of
a potential signature (biomarker) for sensitivity to EGFR inhibitors. Experiments are in progress to validate
these results in high throughput studies in pre-clinical models, with perspectives to move to Phase I/II
studies.
Selected references
Grants
• CIT funded multi-omic analysis and bioinformatics support (>1000K€)
• National and EU funds (various)
Major publications over the past four years
• A Poor Prognosis Subtype of HNSCC Is Consistently Observed across
Methylome, Transcriptome, and miRNome Analysis CLINICAL CANCER
RESEARCH 2013
• Biological and clinical relevance of transcriptionally active human papillomavirus (HPV) infection in oropharynx squamous cell carcinoma INTERNATIONAL JOURNAL OF CANCER 2010
• ANO1 amplification and expression in HNSCC with a high propensity for
future distant metastasis and its functions in HNSCC cell lines BRITISH
JOURNAL OF CANCER 2010
• The Oncogenic MicroRNA Hsa-miR-155-5p Targets the Transcription
Factor ELK3 and Links It to the Hypoxia Response PLOS ONE 2014
102
Molecular and Cellular
Biology of HNSCC and
Prostate Cancer
Bohdan Wasylyk
Business Development Opportunities
Objectives:
• Resolve the lack of new and effective therapeutic options for HNSCC, a prevalent
cancer with poor prognosis.
• Repurpose and improve the use of targeted therapies
Tools:
• State of the art methodology in a world leading institute (IGBMC)
• Large clinically annotated tumour collection at the Strasbourg Cancer Hospital (CPS)
sustained by local prevalence of HNSCC.
• Advanced data mining and bioinformatics capacity, nourished by cross-analysis of large
data sets from many cancers (CIT, Ligue Contre le Cancer).
Unique selling points:
• Unique signature of poor prognosis subgroup of HNSCC, based on a combined 4-omic
analysis of our patient cohort.
• Unique signature to select patients for targeted therapy with EGFR inhibitors.
• Unique capacity to validate and exploit these signatures using our clinical expertise
(patients, tumour samples; CPS, PI: Alain Jung), functional analysis (high throughput
screening, pre-clinical models, PI: B Wasylyk) and data-mining / bioinformatics (CIT, PI:
A De Reynies).
103
Molecular and Cellular
Biology of HNSCC and
Prostate Cancer
Bohdan Wasylyk
Project / Expertise
PrognostaMirs to identify and treat poor prognosis HNSCC
Results
Perspectives
• Validate epigenetic signature of poor prognosis
based on miRNAs and use
them as therapeutic agents
Effective targeted therapy for HNSCC
Results
• The lack of validated predictive biomarkers precludes effective patient
selection for targeted therapies.
• We found a potential biomarker by multi-omic large-dataset analysis.
• One subtype of patients overexpresses EGFR ligands.
• This subtype of HNSCC cell lines responds better to EGFR-inhibitors.
Perspectives
• Develop a clinically useful biomarker to select HNSCC patients for
EGFR-inhibitor therapy and repurposed drug combinations.
• Validate our findings in large patient cohorts and pre-clinical models
(patient samples, xenografts, cancer cell lines, etc).
104
Laboratory « Epigenetic
Regulation of Cell Identity »
headed by Michael Weber
Michael WEBER
Ph.D.
Contact: [email protected]
> Research Center; Town: CNRS UMR7242, Strasbourg
> Administrative affiliations: C
NRS - Université de Strasbourg
> Tech Transfer Office: C NRS Délégation Alsace
www.alsace.cnrs.fr
Keywords:
• DNA methylation
• Methylome
• DNA methyltransferase
• Bisulfite sequencing
• Embryonic development
Synopsis
We employ state-of-the-art genome-wide epigenome technologies and functional tools to study the role of
DNA methylation in the control of normal and malignant cell identities in mammals.
Abstract
Epigenetic marks such as DNA methylation undergo dynamic changes during cell differentiation and their
deregulation is causally involved in many human diseases and the appearance of cancerous phenotypes. Our
objectives are to understand how DNA methylation marks influence gene expression states and contribute to
maintain stable heritable cellular identities. We also aim at identifying factors that maintain or remodel DNA
methylation marks during normal development and cellular transformation. Our scientific questions imply the
use of technologies to map epigenetic marks on a genome-wide scale, combined with bioinformatics analysis
and molecular biology. These techniques are applied on various experimental models such as primary cells,
mouse ES cells, and in vivo mouse models.
Selected references
Grants
• ATIP/Avenir Grant (2011)
• INCa (2014), Plan Cancer (2014)
• ERC Consolidator Grant (2014)
Major publications over the past four years
• Auclair G, Borgel J, Sanz LA, Vallet J, Guibert S, Dumas M, Cavelier P,
Girardot M, Forné T, Feil R, Weber M. EHMT2 directs DNA methylation for
efficient gene silencing in mouse embryos. Genome Res 2015
• Auclair G, Guibert S, Bender A, Weber M. Ontogeny of CpG island methylation and specificity of DNMT3 methyltransferases during embryonic development in the mouse. Genome Biol 2014
• Bender A, Weber M. DNA methylation: an identity card for brain cells.
Genome Biol 2013
• Guibert S, Forné T, Weber M. Global profiling of DNA methylation erasure
in mouse primordial germ cells. Genome Res 2012
• Guibert S, Weber M. Epigenetics: erase for a new start. Nature 2012
• Borgel J, Guibert S, Li Y, Chiba H, Schübeler D, Sasaki H, Forné T, Weber
M. Targets and dynamics of promoter DNA methylation during early mouse
development. Nature Genetics 2010
105
Laboratory « Epigenetic
Regulation of Cell Identity »
headed by Michael Weber
Michael WEBER
Business Development Opportunities
Objectives:
• Map the dynamics of DNA methylation in mammalian cells
• Understand the role of DNA methylation in the maintenance of cell identities
• Identify molecular pathways that remodel DNA methylation patterns
Tools:
• Genome-wide methylomes by NGS (RRBS, WGBS)
• Bioinformatic integration of NGS data (epigenome, transcriptome, cistrome)
• Mouse embryology and genetics
• Genetic and epigenetic engineering in mammalian cells
Unique selling points:
• Our team is a pioneer for the genome-wide analysis of DNA methylation in mammalian
genomes
• We offer a unique expertise for the generation and analysis of methylomes at single
base resolution by Next Generation Sequencing (RRBS, WGBS, ox-BS).
• We master tools for the isolation of embryonic cell populations and genetic manipulation
of DNA methylation in the mouse
106
Laboratory « Epigenetic
Regulation of Cell Identity »
headed by Michael Weber
Michael WEBER
Project / Expertise
Subject 1
Results
• We generated genome-wide maps of DNA methylation acquisition in the mouse embryo and showed
that the enzymes DNMT3A/DNMT3B play both
redundant and specific functions in embryonic DNA
methylation.
Subject 2
Results
• We showed that the histone methyltransferase
EHMT2 (G9a) is critical to recruit repressive DNA
methylation at genes during embryonic development, suggesting a functional interconnection
between histone methylation and DNA methylation
pathways in mammalian development
107
Epigenetics and Cell Fate
Jonathan Weitzman
Ph.D.
Contact: [email protected]
> Research Center; Town: E
pigénétique et Destin Cellulaire
(EDC), Paris
> Administrative affiliations: Université Paris Diderot - CNRS
UMR 7216
> Tech Transfer Office: Idfinnov
www.idfinnov.com
Keywords:
• Lysine Methylation
• Parasite-induced transformation
• microRNA circuitry
Synopsis
We investigate the molecular mechanisms underlying transformation inspired by an innovative parasiteinduced model system.
Abstract
Our team studies the role of Lysine methylation in defining cancer phenotypes and cellular identities. We are
interested in deciphering the epigenetic changes that characterize tumor progression and how infectious
agents hijack the genetic and epigenetic machinery of their host cells to drive tumorigenesis. We use
integrated genomic and proteomic approaches to investigate the enzymes involved in the lysine methylome
in cancer and infected cells and their contribution to the plasticity of cellular phenotypes. Recent projects
have focused on the role of the SMYD3 Histone Methyltransferase in metastasis (Cancer Research 2012),
a regulatory feedback loop driven by the miR-155 oncomiR (PLoS Pathogens 2013), parasite-induced
effects on host metabolism and the Warburg effect (Oncogene 2013) and the role of prolyl isomerization in
oncogenic signalling (Nature 2015).
Selected references
Grants
• Jonathan Weitzman is the co-ordinator of the Laboratoire d’excellence
LABEX Who Am I? an interdisciplinary consortium dedicated to defining the
molecular and cellular basis od identity in health and disease
• Weitzman group received a proof of concept grant from SATT idfinnov for
his work on theileriosis.
Major publications over the past four years
• Cock-Rada AM*, Medjkane S*, Janski N, Yousfi N, Perichon M, Chaussepied M, Chluba J, Langsley G, Weitzman JB. SMYD3 promotes cancer invasion by epigenetic upregulation of the metalloproteinase MMP-9. (2012)
Cancer Research 72:810-20
• Cock-Rada AM, Weitzman JB. The methylation landscape of tumor metastasis. (2013) Biology of the Cell doi: 10.1111/boc.201200029.
• Marsolier J*, Pineau S*, Medjkane S, Perichon M, Yin Q, Flemington E,
Weitzman MD, Weitzman JB. OncomiR addiction is generated by a miR-155
feedback loop in Theileria-transformed leukocytes. (2013) PLoS Pathogens
9(4):e1003222. doi: 10.1371/journal.ppat.1003222
• Medjkane S, Perichon M, Marsolier J, Dairou J, Weitzman JB. Theileria
induces oxidative stress and HIF1α activation that are essential for host
leukocyte transformation (2013) Oncogene doi: 10.1038/onc.2013.134
• Weitzman MD*, Weitzman JB*. What’s the damage? The impact of pathogens on pathways that maintain host genome integrity. (2014) Cell Host
& Microbe 15:283-294. doi:10.1016/j.chom.2014.02.010
• Cheeseman K, Weitzman JB, Medjkane S. L’épigénome au coeur de la
cancérogénèse. (2014) BioFutur 359:44-47
• Marsolier J, Perichon M, DeBarry JD, Villoutreix BO, Chluba J, Lopez T,
Garrido C, Zhou XZ, Lu KP, Fritsch L, Ait-Si-Ali S, Mhadhbi M, Medjkane S,
Weitzman JB. Theileria parasites secrete a prolyl isomerase to maintain host
leukocyte transformation. (2015) Nature 520:378-82
Patents
• WO2015032998, « Pin1 inhibitors for use in the prevention and/or treatment of theileriosis, and related applications », Marsolier J, Weitzman J,
Medjkane S & Perichon M
108
Epigenetics and Cell Fate
Jonathan Weitzman
Business Development Opportunities
Objectives:
• To link signaling pathways to nuclear effects on the epigenome
• To learn lessons from how parasites hijack host cells to drive transformation
• To identify key mechanistic events for potential drug targeting
Tools:
• A battery of in vitro and in vivo assays for tumor growth and invasion
• A platform for functional epigenomic analysis
• Methylome proteomics investigations and genome-wide Chromatin Immunoprecipitation
(ChIP) analysis
Unique selling points :
• A unique parasite-induced transformation model
• Linking infection and tumorigenesis
• Mechanistic insights into oncogenic signaling pathways
• Linking signaling to epigenetic changes in host nucleus
• Testing for small molecule inhibitors
• Developing epigenome-wide analysis of target loci
109
Epigenetics and Cell Fate
Jonathan Weitzman
Project / Expertise
Infection-induced oncogenic signaling pathways
Results
• The intracellular parasite Theileria transforms host leukocytes:
infected TBL3 cells formed colonies when grown in soft agar
and the transformed phenotype
was reversed by incubating with
Buparvaquone (+Bup).
• Infection-induced transformation involves the SMYD3
Histone methyltransferase and
miR155 oncomiR pathways.
• Cock-Rada et al. Cancer Research (2012)
Marsolier et al. PLoS Pathogens
(2013)
Perspectives
• We study the SMYD3 Lysine methyltransferase in a range of human cancer models to identify targets for intervention.
Infection-induced oncogenic signaling pathways
Results
• Theileria-infected cells form tumors in
vivo and tumor growth is inhibited by antiparasite drugs.
• Inhibitors of the Pin1 prolyl isomerase
block Xenograft tumor growth in a zebrafish assay for tumor growth and invasiveness
• Marsolier et al. Nature (2015).
Perspectives
• We are exploring the role of epigenetic
enzymes in parasite-induced transformation
110